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4.3: The Application of Sugar

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.03%3A_The_Application_of_Sugar

Sugar is the third most used ingredient in the bakeshop. Sugar has several functions in baking. The most recognized purpose is, of course, to sweeten food, but there are many other reasons sugar is used in cooking and baking:Just as there are many functions of sugar in the bakeshop, there are different uses for the various types of sugar as well:This page titled 4.3: The Application of Sugar is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.4: Agave

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.04%3A_Agave

Agave has gained popularity in the food industry due to some of its nutritional properties. The agave nectar is obtained from the sap of the heart of the agave plant, a desert succulent, which is also used to produce tequila. The syrup/sugar production process of agave is similar to that of sugar. See more about the nutritional properties and application of agave in the chapter Special Diets, Allergies, Intolerances, Emerging Issues, and Trends in the open textbook Nutrition and Labelling for the Canadian Baker.A video on the production of agave syrup is availableThis page titled 4.4: Agave is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.6: Honey

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.06%3A_Honey

Honey is a natural food, essentially an invert sugar. Bees gather nectar and, through the enzyme invertase, change it into honey. Honey varies in composition and flavor depending on the source of the nectar. The average composition of honey is about 40% levulose, 35% dextrose, and 15% water, with the remainder being ash, waxes, and gum.Blended honey is a mixture of pure honey and manufactured invert sugar, or a blend of different types of honey mixed together to produce a good consistency, color, and aroma. Dehydrated honey is available in a granular form.Store honey in a tightly covered container in a dry place and at room temperature because it is hygroscopic, meaning it absorbs and retains moisture. Refrigeration or freezing won’t harm the color or flavor but it may hasten granulation. Liquid honey crystallizes during storage and is re-liquefied by warming in a double boiler not exceeding a temperature of 58°C (136°F).Honey is used in baking:There are several types of honey available:In the United States, honey categories are based on color, from white to dark amber. Honey from orange blossom is an example of white honey. Clover honey is an amber honey, and sage and buckwheat honeys are dark amber honeys.This page titled 4.6: Honey is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.7: Malt

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.07%3A_Malt

Malt is the name given to a sweetening agent made primarily from barley. The enzymes from the germ of the seeds become active, changing much of the starch into maltose, a complex sugar. Maltose has a distinct flavor and is used for making yeast products such as bread and rolls. Malt is considered to be relatively nutritious compared to other sweeteners.Malt is available as:The flour is not recommended since it can lead to problems if not scaled precisely. Malt syrup is inconvenient to work with, as it is sticky, heavy, and bulky. Dried malt is the most practical, though it must be kept protected from humidity.There are two distinct types of malt:Crushing malted grain in water produces malt syrup. This dissolves the maltose and soluble enzymes. The liquid is concentrated, producing the syrup. If the process is continued, a dry crystallized product called dried malt syrup is obtained.Malt syrup has a peculiar flavor, which many people find desirable. It is used in candy, malted milk, and many other products. The alcoholic beverage industry is the largest consumer of malt by far, but considerable quantities are used in syrup and dried malt syrup, both of which are divided into diastatic and non-diastatic malt.Both diastatic and non-diastatic malts add sweetness, color, and flavor to baked products. Both are valuable since they contain malt sugar, which is fermented by the yeast in the later stages of fermentation. Other sugars such as glucose and levulose are used up rapidly by fermenting yeast in the early stages of fermentation. Diastatic malt is made with various levels of active enzymes. Malt with medium diastatic activity is recommended. Normally, bread bakers will find sufficient enzymes in well-balanced flour from a good mill, so it is unnecessary to use diastatic malt.When using dry diastatic malt, about the same weight should be used as liquid regular diastatic malt. Adjustment is made at the factory insofar as the enzyme level is increased in the dry product to compensate. Since the dry type contains about 20% less moisture than the liquid type, add water to make up the difference if dry diastatic malt is substituted for malt syrup.The main uses of malt in the bakery are to:Table 1 shows the suggested use levels for malt.This page titled 4.7: Malt is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.8: Maple Syrup (ADD US)

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.08%3A_Maple_Syrup_(ADD_US)

Canada is responsible for 84% of the world’s maple syrup production, with the United States being responsible for the remaining 16%. Maple syrup is made by boiling and evaporating the sap of the sugar maple tree. Because sap is only 2% or 3% sugar, it takes almost 40 liters of sap to make 1 liter of syrup. This makes maple syrup a very expensive sweetener. It is prized for its unique flavor and sweet aroma. Don’t confuse maple-flavored pancake or table syrup with real maple syrup. Table syrup is made from inexpensive glucose or corn syrup, with added caramel coloring and maple flavoring.Maple syrup in Canada has two categories:This definition and grading system gives consumers more consistent and relevant information about the varieties, and helps them make informed choices when choosing maple syrup.Darker maple syrups are better for baking as they have a more robust flavor. Using maple sugar is also a good way to impart flavor. Maple sugar is what remains after the sap of the sugar maple is boiled for longer than is needed to create maple syrup. Once almost all the water has been boiled off, all that is left is a solid sugar. It can be used to flavor some maple products and as an alternative to cane sugar.For a video on maple syrup production, see: //www.youtube.com/watch?v=OFIj4pMYpTQ This page titled 4.8: Maple Syrup (ADD US) is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.9: Sugar Substitutes (ADD US)

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.09%3A_Sugar_Substitutes_(ADD_US)

In Canada, food additives such as sugar substitutes, which cover both artificial sweeteners and intense sweeteners obtained from natural sources, are subject to rigorous controls under theFood and Drugs Act and Regulations. New food additives (or new uses of permitted food additives) are permitted only once a safety assessment has been conducted and regulatory amendments have been enacted.Several sugar substitutes have been approved for use in Canada. These include acesulfame-potassium, aspartame, polydextrose, saccharin, stevia, sucralose, thaumatin, and sugar alcohols (polyols) like sorbitol, isomalt, lactitol, maltitol, mannitol, and xylitol. Please see the Health Canada website for more information on sugar substitutes.Bakers must be careful when replacing sugar (sucrose) with these sugar substitutes in recipes. Even though the sweetness comparison levels may be similar (or less), it is generally not possible to do straight 1-for-1 substitution. Sugar (sucrose) plays many roles in a recipe:Sugar substitutes may not work in a recipe in the same way. More information on sugar substitutes and their relative sweetness can be found here: http://www.sugar-and-sweetener-guide...er-values.htmlThis page titled 4.9: Sugar Substitutes (ADD US) is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4.5: Glucose/Dextrose

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/04%3A_Sugar/4.5%3A_Glucose%2F%2FDextrose

The sugar known as glucose has two origins:In baking, we usually refer to industrially made glucose. It is made from corn and the resulting product, a thick syrup, is then adjusted to a uniform viscosity or consistency. The particular form of the syrup is defined by what is known as the dextrose equivalent, or DE for short. Corn syrup is the most familiar form of glucose.In plant baking, high-fructose corn syrup (HFCS) is the major sweetening agent in bread and buns. It consists of roughly half fructose and half dextrose. Dextrose (chemically identical to glucose) is available in crystalline form and has certain advantages over sucrose:Corn syrup is made from the starch of maize (corn) and contains varying amounts of glucose and maltose, depending on the processing methods. Corn syrup is used in foods to soften texture, add volume, prevent crystallization of sugar, and enhance flavor.Glucose/dextrose has a sweetening level of approximately three-quarters that of sugar. Table 1 shows the amount of corn syrup or HFCS needed to replace sugar in a formula. Glucose, HFCS, and corn syrup are not appropriate substitutions for sucrose in all bakery products. Certain types of cakes, such as white layer cakes, will brown too much if glucose or HFCS is used in place of sugar. This page titled 4.5: Glucose/Dextrose is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.1: Introduction to Leavening Agents

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.01%3A_Introduction_to_Leavening_Agents

The word leavening in the baking trade is used to describe the source of gas that makes a dough or batter expand in the presence of moisture and heat. Leavening agents are available in different forms, from yeast (the organic leavener) to chemical, mechanical, and physical leaveners. Bakers choose the appropriate type of leavening based on the product they are making.This page titled 5.1: Introduction to Leavening Agents is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.2: Yeast

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.02%3A_Yeast

Yeast is a microscopic unicellular fungus that multiplies by budding, and under suitable conditions, causes fermentation. Cultivated yeast is widely used in the baking and distilling industries. History tells us that the early Chaldeans, Egyptians, Greeks, and Romans made leavened bread from fermented doughs. This kind of fermentation, however, was not always reliable and easy to control. It was Louis Pasteur, a French scientist who lived in the 19th century, who laid the foundation for the modern commercial production of yeast as we know it today through his research and discoveries regarding the cause and prevention of disease.Wild yeast spores are found floating on dust particles in the air, in flour, on the outside of fruits, etc. Wild yeasts form spores faster than cultivated yeasts, but they are inconsistent and are not satisfactory for controlled fermentation purposes.Compressed yeast is made by cultivating a select variety, which is known by experiment to produce a yeast that is hardy, consistent, and produces a fermentation with strong enzymatic action. These plants are carefully isolated in a sterile environment free of any other type of yeast and cultivated on a plate containing nutrient agar or gelatin. Wort, a combination of sterilized and purified molasses or malt, nitrogenous matter, and mineral salts is used to supply the food that the growing yeast plants need to make up the bulk of compressed yeast.After growing to maturity in the fermentation tank, the yeast is separated from the used food or wort by means of centrifugal machines. The yeast is then cooled, filtered, pressed, cut, wrapped, and refrigerated. It is marketed in 454 g (1 lb.) blocks, or in large 20 kg (45 lb.) bags for wholesale bakeries.illustrates the process of cultivating compressed yeast, and Table 1 summarizes its composition. Cultivating compressed yeastActive dry yeast is made from a different strain than compressed yeast. The manufacturing process is the same except that the cultivated yeast is mixed with starch or other absorbents and dehydrated. Its production began after World War II, and it was used mainly by the armed forces, homemakers, and in areas where fresh yeast was not readily available.Even though it is a dry product, it is alive and should be refrigerated below 7°C (45°F) in a closed container for best results. It has a moisture content of about 7%. Storage without refrigeration is satisfactory only for a limited period of time. If no refrigeration is available, the yeast should be kept unopened in a cool, dry place. It should be allowed to warm up to room temperature slowly before being used.Dry yeast must be hydrated for about 15 minutes in water at least four times its weight at a temperature between 42°C and 44°C (108°F and112°F). The temperature should never be lower than 30°C (86°F), and dry yeast should never be used before it is completely dissolved.It takes about 550 g (20 oz.) of dry yeast to replace 1 kg (2.2 lb.) of compressed yeast, and for each kilogram of dry yeast used, an additional kilogram of water should be added to the mix. This product is hardly, if ever, used by bakers, having been superseded by instant yeast (see below).Instant Dry YeastUnlike instant active dry yeast that must be dissolved in warm water for proper rehydration and activation, instant dry yeast can be added to the dough directly, either by:Mixing it with the flour before the water is addedAdding it after all the ingredients have been mixed for one minuteThis yeast can be reconstituted. Some manufacturers call for adding it to five times its weight of water at a temperature of 32°C to 38°C (90°F to 100°F). Most formulas suggest a 1:3 ratio when replacing compressed yeast with instant dry. Others vary slightly, with some having a 1:4 ratio. it takes about 400 g (14 oz.), and in bread dough about 250 g to 300 g (9 oz. to 11 oz.) of instant dry yeastto replace 1 kg (2.2 lb.) of compressed yeast. As well, a little extra water is needed to make up for the moisture in compressed yeast. Precise instructions are included with the package; basically, it amounts to the difference between the weight of compressed yeast that would have been used and the amount of dry yeast used.Instant dry yeast has a moisture content of about 5% and is packed in vacuum pouches. It has a shelf life of about one year at room temperature without any noticeable change in its gassing activity. After the seal is broken, the content turns into a granular powder, which should be refrigerated and used by its best-before date, as noted on the packaging.Instant dry yeast is especially useful in areas where compressed yeast is not available. However, in any situation, it is practical to use and has the advantages of taking up less space and having a longer shelf life than compressed yeast.Cream YeastCreamy yeast is a soft slurry-type yeast that is used only in large commercial bakeries and is pumped into the dough.Yeast FoodYeast food is used in bread production to condition the dough and speed up the fermentation process. It consists of a blend of mineral salts such as calcium salt or ammonium salt and potassium iodate. It has a tightening effect on the gluten and is especially beneficial in dough where soft water is used. The addition of yeast food improves the general appearance and tasting quality of bread. The retail baker does not use it much.This page titled 5.2: Yeast is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.3: The Functions of Yeast

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.03%3A_The_Functions_of_Yeast

Yeast has two primary functions in fermentation:To convert sugar into carbon dioxide gas, which lifts and aerates the dough To mellow and condition the gluten of the dough so that it will absorb the increasing gases evenly and hold them at the same timeIn baked products, yeast increases the volume and improves the flavor, texture, grain, color, and eating quality. When yeast, water, and flour are mixed together under the right conditions, all the food required for fermentation is present as there is enough soluble protein to build new cells and enough sugar to feed them.Activity within the yeast cells starts when enzymes in the yeast change complex sugar into invert sugar. The invert sugar is, in turn, absorbed within the yeast cell and converted into carbon dioxide gas and alcohol. Other enzymes in the yeast and flour convert soluble starch into malt sugar, which is converted again by other enzymes into fermentable sugar so that aeration goes on from this continuous production of carbon dioxide.Proper Handling of YeastCompressed yeast ages and weakens gradually even when stored in the refrigerator. Fresh yeast feels moist and firm, and breaks evenly without crumbling. It has a fruity, fresh smell, which changes to a sticky mass with a cheesy odor. It is not always easy to recognize whether or not yeast has lost enough of its strength to affect the fermentation and the eventual outcome of the baked bread, but its working quality definitely depends on the storage conditions, temperature, humidity, and age.The optimum storage temperature for yeast is -1°C (30°F). At this temperature it is still completely effective for up to two months. Yeast does not freeze at this temperature.Other guidelines for storing yeast include:Rotating it properly and using the older stock first Avoiding overheating by spacing it on the shelves in the refrigeratorYeast needs to breathe, since it is a living fungus. The process is continuous, proceeding slowly in the refrigerator and rapidly at the higher temperature in the shop. When respiration occurs without food, the yeast cells starve, weaken, and gradually die.Yeast that has been frozen and thawed does not keep and should be used immediately. Freezing temperatures weaken yeast, and thawed yeast cannot be refrozen successfully.This page titled 5.3: The Functions of Yeast is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.4: Using Yeast in Baking

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.04%3A_Using_Yeast_in_Baking

Many bakers add compressed yeast directly to their dough. A more traditional way to use yeast is to dissolve it in lukewarm water before adding it to the dough. The water should never be higher than 50°C (122°F) because heat destroys yeast cells. In general, salt should not come into direct contact with yeast, as salt dehydrates the yeast. (Table 1 indicates the reaction of yeast at various temperatures.)It is best to add the dissolved yeast to the flour when the dough is ready for mixing. In this way, the flour is used as a buffer. (Buffers are ingredients that separate or insulate ingredients, which if in too close contact, might start to react prematurely.) In sponges where little or no salt is used, yeast buds quickly and fermentation of the sponge is rapid.Never leave compressed yeast out for more than a few minutes. Remove only the amount needed from the refrigerator. Yeast lying around on workbenches at room temperature quickly deteriorates and gives poor results. One solution used by some bakeries to eliminate steps to the fridge is to have a small portable cooler in which to keep the yeast on the bench until it is needed. Yeast must be kept wrapped at all times because if it is exposed to air the edges and the corners will turn brown. This condition is known as air- burn.This page titled 5.4: Using Yeast in Baking is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.5: Baking Powder

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.05%3A_Baking_Powder

Baking powder is a dependable, high-quality chemical leavener. To be effective, all baking powders rely on the reaction between one or more acids on sodium bicarbonate to produce carbon dioxide gas. Just as with yeast leavening, the presence of carbon dioxide gas creates air bubbles that cause the product to rise.There are two main types of baking powders available on the market:The difference between continuous- and double-action baking powders is simply the rate of reaction:Before baking, approximately 15% of the CO2 gas is released in the cold stage. Eighty-five percent of the CO2 gas is released in the oven starting at approximately 40°C (105°F). Some leavening power is apparently lost in the cold stage, but there is usually still adequate gassing power in the remaining portion.When the baking powder is activated through moisture and heat, the gas works its way into the many cells created by the mixing or creaming of the batter and starts to expand them. This process comes to a halt when the starch gelatinizes and the cells become rigid. This starts at about 60°C (140°F) and is more or less complete at around 75°C (167°F). After this point, some gas may still be created, but it simply escapes through the porous structure of the product.For even distribution throughout the batter, baking powder should be sifted with the flour or other dry ingredients. For most cakes, about 5% baking powder to the weight of the flour produces an optimum result. Accurate scaling is important, since a little too much may cause the product to collapse. (Note this is unlike yeast, where an “overdose” will usually simply cause a more rapid rise.)This page titled 5.5: Baking Powder is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.6: Sodium Bicarbonate

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.06%3A_Sodium_Bicarbonate

When sodium bicarbonate (baking soda) is moistened and heated, it releases carbon dioxide gas. If it is moistened and heated in the presence of sufficient acid, it will release twice as much gas as if it is moistened and heated without the presence of an acid.Slightly acidic ingredients provide the mix with some of the necessary acids for the release of carbon dioxide gas. Examples are:Honey Molasses Ginger Cocoa BranFor this reason, some of the mixes contain baking powder only while others contain a combination of baking powder and baking soda. If an excessive amount of baking soda is used in a cake batter without the presence of sufficient acid, the normally white cake crumb will have a yellowish-brown color and a strong undesirable smell of soda.The gas evolves very fast at the beginning of baking when thepH level is still on the acidic side (pH of around 5 to 6). Once the soda neutralizes the acid, the dough or batter quickly becomes alkaline and the release of gas is reduced. Mixes and doughs leavened with baking soda must be handled without delay, or the release of the gas may be almost exhausted before the product reaches the oven.The darker color of the crumb found on the bottom half of a cake or muffins is caused by the partial dehydration of the batter that is heated first during baking. In spiced honey cookies and gingerbread, baking soda is used alone to give them quick color during baking and yet keep the products soft.In chocolate cakes, baking soda is used in conjunction with baking powder to keep the pH at a desirable level. However, it is important to know whether the cocoa powder you are using is natural or treated by the Dutch process. In the Dutch process, some of the acid in the cocoa is already neutralized, and there is less left for the release of gas in the mix. This means more baking powder and less baking soda is used.Baking soda in a chocolate mix not only counteracts the acid content in the baked cake but also improves the grain and color of the cake. A darker and richer chocolate color is produced if the acid level is sufficient to release all the carbon dioxide gas. On the other hand, the reddish, coarse, open-grained crumb in devil’s food cake is the result of using baking soda as the principal leavening agent.The level of baking soda depends on the nature of the product and on the other ingredients in the formula. Cookies, for example, with high levels of fat and sugar, do not require much, if any, leavening.Table 1 provides the recommended amounts of baking soda for different products. contains both an acid agent and a leavening agent. This page titled 5.6: Sodium Bicarbonate is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.7: Ammonium Bicarbonate

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.07%3A_Ammonium_Bicarbonate

Ammonium bicarbonate is a white crystalline powder used in flat, spiced cookies, such as gingerbreads, and in eclair paste. It must be dissolved in the cold liquid portion of the batter. At room temperature, decomposition of \(\ce{CO2}\) in the batter is minimal. When heated to approximately 60°C (140°F) decomposition is more noticeable, and at oven temperature, decomposition takes place in a very short time. Ammonium bicarbonate should only be used in low moisture-containing products that are not dense. Providing that these conditions are met, there will be no taste and odor remaining from the ammonium.This page titled 5.7: Ammonium Bicarbonate is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5.8: Water Hardness and pH

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/05%3A_Leavening_Agents/5.08%3A_Water_Hardness_and_pH

Most municipal supplies of water contain chlorine, which is used to ensure the purity of the water. Some cities add fluoride to their water supply to stop tooth decay. Neither chlorine nor fluoride is present in large enough quantities to affect dough in any way. In addition, most municipal water is treated to reduce excessive acidity, since this could be corrosive for the water lines. It is therefore unlikely that bakers using municipal water need to be concerned about extremely acidic water.Soft water is another matter, as it can lead to sticky dough. An addition of yeast food, or a reduction in dough water, will help. Alkaline water tends to tighten the dough and retard fermentation, since enzymes work best in slightly acidic dough.If there is a possibility of water problems, a sample should be forwarded to a laboratory for a complete analysis.This page titled 5.8: Water Hardness and pH is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.1: Introduction to Dairy Products

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Chemistry_of_Cooking_(Rodriguez-Velazquez)/06%3A_Dairy_Products/6.01%3A_Introduction_to_Dairy_Products

Milk and milk products are some of our oldest and best-known natural foods. In baking, milk is used fresh, condensed, powdered, skimmed, or whole. The great bulk, weight, and perishability of fresh milk plus the expense of refrigeration makes it a relatively high-cost ingredient, and for this reason, most modern bakeries use non-fat powdered milk or buttermilk powder.Over the past 20 years, there has been a trend to lower fat content in dairy products. This reflects the high caloric value of milk fat, and also is compatible with the trend to leaner, healthier nutrition. in a recipe. For bakers, this trend has not meant any great changes in formulas: a 35% milk fat or a 15% cream cheese product usually works equally well in a cheesecake. Some pastry chefs find lowering the richness in pastries and plated desserts can make them more enjoyable, especially after a large meal.Table 1 provides the nutritional properties of milk products.Note: Besides the elements shown in Table 1, all dairy products contain vitamin B-complex. IU = International Units, a term used in nutritional measurementThis page titled 6.1: Introduction to Dairy Products is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.2: Milk

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Homogenized milkis fresh milk in which the fat particles are so finely divided and emulsified mechanically that the milk fat cannot separate on standing. The milk fat is forced into tiny droplets. As soon as the droplets form, milk proteins and emulsifiers form a protective film around each one, preventing the fat from reuniting. The tiny droplets stay suspended indefinitely, and milk fat no longer separates and risesto the top as a cream layer. In other words, homogenized dairy products are stable emulsions of fat droplets suspended in milk. It is also said that homogenized milk is more readily digestible.Pasteurization of milk was developed in 1859 by the French chemist Louis Pasteur. One method of pasteurization is to heat milk to above 71°C (160°F), maintain it at this temperature for a set time, then cool it immediately to 10°C (50°F) or lower. This kills all harmful bacteria that carry the potential threat of bovine tuberculosis and fever from cows to humans.The two main types of pasteurization used today are high-temperature, short-time (HTST, also known as “flash”) and higher-heat, shorter time (HHST). Ultra-high-temperature (UHT) processing is also used.High-temperature, short-time (HTST) pasteurization is done by heating milk to 72°C (161°F) for 15 seconds. Milk simply labelled “pasteurized” is usually treated with the HTST method. Higher-heat, shorter time (HHST) milk and milk products are pasteurized by applying heat continuously, generally above 100°C (212°F) for such time to extend the shelf life of the product under refrigerated conditions. This type of heat process can be used to produce dairy products with extended shelf life (ESL).Ultra-high-temperature (UHT) processing holds the milk at a temperature of 140°C (284°F) for four seconds. During UHT processing, milk is sterilized rather than pasteurized. This process allows milk or juice to be stored several months without refrigeration. The process is achieved by spraying the milk or juice through a nozzle into a chamber that is filled with high-temperature steam under pressure. After the temperature reaches 140°C (284°F) the fluid is cooled instantly in a vacuum chamber and packed in a pre-sterilized, airtight container. Milk labelled UHT has been treated in this way.For more information on pasteurization, visit the International Dairy Foods Association. Attribution This page titled 6.2: Milk is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.3: Milk Products ADD US

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CreamThe usual minimum standard for cream is 10% fat content, though it ranges between 10% and 18%. Cream in this range may be sold as half and half, coffee cream, or table cream.Whipping cream is about 32% to 36% in milk fat content. Cream with 36% or higher is called heavy cream. This percentage of fat is not a mandated standard; much less than this and the cream simply will not whip. For best whipping results, the cream should be 48 to 60 hours old and be cold. A stabilizer, some sugar, and flavour may be added during whipping. Before adding stabilizer, check the ingredients on the carton; some whipping creams nowadays have added agents such as carrageenan, in which case an additional stabilizer may not be necessary.Canadian cream definitions are similar to those used in the United States, except for that of “light cream.” In Canada, what the U.S. calls light cream is referred to most commonly as half and half. In Canada, “light cream” is low-fat cream, usually with 5% to 6% fat. You can make your own light cream by blending milk with half-and-half.In Quebec, country cream is sold, which contains 15% milk fat. If you are usinga recipe that calls for country cream, you may substitute 18% cream.If you have recipes from the UK, you might see references to double cream. This is cream with about 48% milk fat, which is not readily available in Canada, except in some specialty stores. Use whipping cream or heavy cream instead.Table 1 lists some of the common cream types and their uses.ButtermilkInoculating milk with a specific culture to sour it Churning milk and separating the liquid left over from the butterThere are two methods to produce buttermilk: The second method is where buttermilk gets its name, but today, most of what is commonly called buttermilk is the first type. Buttermilk has a higher acid content than regular milk (pH of 4.6 compared with milk’s pH of 6.6).The fermented dairy product known ascultured buttermilk is produced from cow’s milk and has a characteristically sour taste caused by lactic acid bacteria. This variant is made using one of two species of bacteria — either Lactococcus lactis or Lactobacillus bulgaricus, which creates more tartness in certain recipes.The acid in buttermilk reacts with the sodium bicarbonate (baking soda) to produce carbon dioxide, which acts as the leavening agent.Sour cream is made from cream soured by adding lactic acids and thickened naturally or by processing. Milk fat content may vary from 5.5% to 14%. The lactic acid causes the proteins in sour cream to coagulate to a gelled consistency; gums and starches may be added to further thicken it. The added gums and starches also keep the liquid whey in sour cream from separating.Use sour cream in cheesecakes, coffee cakes, and pastry doughs. Low-fat and fat-free sour cream are available. Low-fat sour cream, which is essentially cultured half-and-half or light cream (and usually contains 7% to 10% milk fat), is often satisfactory as a substitute for regular sour cream in baking. These products are higher in moisture and less rich in flavor than regular sour cream.Crème fraîche (fresh cream) is a soured cream containing 30% to 45% milk fat and having a pH of around 4.5. It is soured with bacterial culture. Traditionally it is made by setting unpasteurized milk into a pan at room temperature, allowing the cream to rise to the top. After about 12 hours, the cream is skimmed off. During that time, natural bacteria in the unpasteurized milk ripens the cream, turning it into a mildly sour, thickened product.An effective substitute can be made by adding a small amount of cultured buttermilk or sour cream to whipping cream and allowing it to stand in a warm spot for 10 hours or more before refrigerating. As the cream ripens from the growth of the lactic acid bacteria, it thickens and develops a sour flavour. This product is similar to sour cream, but it has a higher milk fat content.Milk substitutes are becoming increasingly popular as replacements for straight skim milk powders. Innumerable replacement blends are available to the baker. Their protein contents range from 11% to 40%; some are wet, some are dry-blended. Product types vary from all dairy to mostly cereal. All-dairy blends range from mostly dry skim milk to mostly whey. A popular blend is whey mixed with 40% soy flour solids and a small quantity of sodium hydroxide to neutralize the whey acidity.Dough consistency may be a little softer if the milk in the replacement blend exceeds 3%, and this could dictate the need to increase dough mixing by at least half a minute. However, absorption and formula changes are seldom necessary when switching from dry milk to a blend, or from a blend to a blend.For nutritional labelling, or when using a blend in a non-standardized product that must carry an itemized ingredient label, all blend components must be listed in their proper order on the label.The Canadian Food Inspection Agency defines modified milk ingredients as any of the following in liquid, concentrated, dry, frozen, or reconstituted form:Calcium-reduced skim milk Casein: This a protein in milk and is used as a binding agent. Caseins are also used in wax to shine fruits and vegetables, as an adhesive, and to fortify bread. Caseins contain common amino acids. Caseinate: This protein is derived from skim milk. Bodybuilders sometimes take powder enriched with calcium caseinate because it releases proteins at an even, measured pace. Cultured milk products: These are milk products that have been altered through controlled fermentation, including yogurt, sour cream, and cultured buttermilk. Ultra-filtered milk: The Canadian Food and Drug Regulations define this type of milk as that which “has been subjected to a process in which it is passed over one or more semi-permeable membranes to partially remove water, lactose, minerals, and water-soluble vitamins without altering the whey protein-to-casein ratio and that results in a liquid product.”Whey: This is serum by-product created in the manufacture of cheese. Whey butter: Typically oily in composition, whey butter is made from cream separated from whey. Whey cream: This is cream skimmed from whey, sometimes used as a substitute for sweet cream and butter. Any component of milk that has been altered from the form in which it is found in milk.Milk powder is available in several different forms: whole milk, skim milk (non-fat dry milk), buttermilk, or whey. They are all processed similarly: the product is first pasteurized, then concentrated with an evaporator, and finally dried (spray or roller dried) to produce powder.Whole milk powder must contain no less than 95% milk solids and must not exceed 5% moisture. The milk fat content must be no less than 2.6%. Vitamins A and D may be added and the emulsifying agent lecithin may also be added in an amount not exceeding 0.5%. Skim milk powder (non-fat dry milk) must contain no less than 95% milk solids and must not exceed 4% moisture or 1.5% fat. Buttermilk powder must contain no less than 95% milk solids and must not exceed 3% moisture or 6% fat. Whey powder consists primarily of carbohydrate (lactose), protein (several different whey proteins, mainly lactalbumins and globulins), various minerals, and vitamins. Whey powder is a valuable addition to the functional properties of various foods as well as a source of valuable nutrients because it contains approximately 50% of the nutrients in the original milk.Table 2 compares the composition of milk and two powdered milk products. To make 10 L (22 lb.) of liquid skim milk from skim milk powder, 9.1 L (2.4 gal.) of water and 900 g (2 lb.) of skim milk powder are required. To make 10 L (22 lb.) of whole milk from skim milk powder, 8.65 L (2.25 gal) of water, 900 g (2 lb.) of skim milk powder, and 450 g (1 lb.) of butter are needed.When reconstituting dried milk, add it to the water and whisk in immediately. Delaying this, or adding water to the milk powder, will usually result in clogging. Water temperature should be around 21°C (70°F). Sometimes called concentrated milk, this includes evaporated whole, evaporated partly skimmed, and evaporated skim milks, depending on the type of milk used in its production. Canadian standards require 25% milk solids and 7.5% milk fat.All types of evaporated milk have a darker color than the original milk because at high temperatures a browning reaction occurs between the milk protein and the lactose. After 60% of the water is removed by evaporation, the milk is homogenized, cooled, restandardized, and canned. It is then sterilized by heating for 10 to 15 minutes at 99°C to 120°C (210°F to 248°F). Controlled amounts of disodium phosphate and/or sodium citrate preserve the “salt balance” and prevent coagulation of the milk that might occur at high temperatures and during storage.Sweetened Condensed MilkSweetened condensed milk is a viscous, sweet-colored milk made by condensing milk to one-third of its original volume, which then has sugar added. It contains about 40% sugar, a minimum of 8.5% milk fat, and not less than 28% total milk solids. Attribution This page titled 6.3: Milk Products ADD US is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.4: Milk in bread baking

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In the dough stage, milk increases water absorption. Consequently, dough made with milk should come softer from the mixer than dough made with water. Other aspects of milk in yeast doughs include:Dough may be mixed more intensively. Milk yields dough with a higher pH compared to water dough, and the fermentation will be slower. Fermentation tolerance (the ability of the dough to work properly in a range of temperatures) will be slightly improved. Bench time will be extended as the dough ferments more slowly at this stage. (Final proof times will be about the same, as by this time the yeast has adjusted to the condition of the dough.)Bread made with milk will color faster in the oven and allowance should be made for this. If taken out too early after a superficial examination of crust color, it may collapse slightly and be hard to slice. The loaf should be expected to have a darker crust color than bread made without milk.In the finished product, milk will make bread that has:Greater volume (improved capacity to retain gas) Darker crust (due to the lactose in the milk) Longer shelf life (due partly to the milk fat) Finer and more “cottony” grainBetter slicing due to the finer grainIf skim milk or skim milk powder is used, some of the above benefits will not be so evident (e.g., longer shelf life, which is a result of the fat in the milk).The type of sugar found in milk, lactose, has little sweetening power and does not ferment, so in dough made with skim milk powder, sugar has to be added or the fermentation will be very slow. While lactose is not fermentable, it caramelizes readily in the oven and produces a healthy crust color. The recommended amount of skim milk powder used in fermented dough is 2% to 8% based on flour, and up 15% in cakes.Buttermilk and sour milk are used to make variety breads. They have a lower pH and require a shorter fermentation for good results.This page titled 6.4: Milk in bread baking is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.5: Yogurt

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Yogurt is a thick or semi-solid food made from pasteurized milk fermented by lactic bacteria. The milk coagulates when a sufficient quantity of lactic acid is produced. Yogurt is a rich, versatile food capable of enhancing the flavor and texture of many recipes. It is prepared sweetened or unsweetened, and is used in baking to make yogurt-flavored cream cakes, desserts, and frozen products. This page titled 6.5: Yogurt is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.6: Lactose

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Lactose is a "milk sugar" and is a complex sugar. It is available commercially spray-dried and in crystalline form. There are many advantages to using it in various baking applications:Because of its low sweetening value compared to sucrose, it can lend texture and create browning while keeping the sweetness level at low values, which many consumers prefer. It can be used to replace sucrose up to a 50% level, or replace it entirely in products like pie pastry. Lactose improves dough handling properties and the color of the loaf.In pie crusts, it gives good color to top and bottom crusts, more tender crusts, and retards sogginess. In machine-dropped cookies, lactose can help the dough release better from the die. In cakes and muffins, it gives body without excessive sweetening and improves volume. Lactose binds flavors that are normally volatile and thus intensifies or enhances flavor. This page titled 6.6: Lactose is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6.7: Cheese

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Cheese is a concentrated dairy product made from fluid milk and is defined as the fresh or matured product obtained by draining the whey after coagulation of casein.Cheese making consists of four steps:Cheese can be classified, with some exceptions, into five broad categories, as follows. Examples are given of specific cheeses that may be used in baking.In baking, cheeses have different functions. for pastries and coffeecakes. They are used for certain European deep-fried goods, such as cannoli. They may also be used, sometimes in combination with a richer cream cheese, for cheesecakes. All the cheeses itemized under fresh cheese (see above) are all more or less interchangeable for these functions. The coarser cheese may be strained first if necessary. The firmer cheeses are used in products like cheese bread, quiches, pizza, and cheese straws.A brief description of the cheeses most likely to be used by bakers follows.This is a soft, unripened, acid cheese. Pasteurized skim milk is inoculated with lactic-acid-producing bacteria, and a milk-clotting enzyme (rennet) is added. Following incubation, the milk starts to clot, and it is then cut into cubes. After gentle cooking, the cubes or curds become quite firm. At this point, the whey is drained off, and the curd is washed and cooled with cold water.Creamed or dressed cottage cheese consists of dry curd cottage cheese combined with a cream dressing. The milk fat content of the dressing determines whether the final product is “regular” (4% milk fat ) or low fat (1% to 2% milk fat).This is a soft, unripened, uncooked cheese. It is made following exactly the same process as for dry curd cottage cheese, up to and including the point when the milk clot is cut into cubes. This cheese is not cooked to remove the whey from the curd. Rather, the curd is drained through cloth bags or it may be pumped through a curd concentrator. The product is then ready to be packaged. The milk fat content is Chemistry of Cooking 214generally about 4%.Quark (or quarg) is a fresh unripened cheese prepared in a fashion similar to cottage cheese. The mild flavor and smooth texture of quark make it excellent as a topping or filling for a variety of dishes. Quark is similar to baker’s cheese, except acid is added to it (it is inoculated with lactic-acid-producing bacteria), and then it is blended with straight cream to produce a smooth spread containing approximately 7% milk fat. Today there are low-fat quarks with lower percentage, and high-fat versions with milk fat adjusted to 18%. Quark cheese can often be used in place of sour cream, cottage cheese, or ricotta cheese.Cream CheeseCream cheese is a soft, unripened, acid cheese. A milk-and-cream mixture is homogenized and pasteurized, cooled to about 27°C (80°F), and inoculated with lactic-acid-producing bacteria. The resulting curd is not cut, but it is stirred until it is smooth, and then heated to about 50°C (122°F) for one hour. The curd is drained through cloth bags or run through a curd concentrator. Regular cream cheese is fairly high fat, but much lighter versions exist now.Ricotta is a fresh cheese prepared from either milk or whey that has been heated with an acidulating agent added. Traditionally lemon juice or vinegar was used for acidulation, but in commercial production, a bacterial culture is used. The curds are then strained and the ricotta is used for both sweet and savory applications.Mascarpone is a rich, fresh cheese that is a relative of both cream cheese and ricotta cheese. Mascarpone is prepared in a similar fashion to ricotta, but using cream instead of whole milk. The cream is acidified (often by the direct addition of tartaric acid) and heated to a temperature of 85°C (185°F), which results in precipitation of the curd. The curd is then separated from the whey by filtration or mechanical means. The cheese is lightly salted and usually whipped. Note that starter culture and rennet are not used in the production of this type of cheese. The high-fat content and smooth texture of mascarpone cheese make it suitable as a substitute for cream or butter. Ingredient applications of mascarpone cheese tend to focus on desserts. The most famous application of mascarpone cheese is in the Italian dessert tiramisu.Table 1 provides the composition of various types of cheeses.This page titled 6.7: Cheese is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7.1: Eggs Grade

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Fresh hen eggs are sold by grade in all provinces. All shell eggs that are imported, exported, or shipped from one province to another for commercial sale must be graded. In Canada, it is mandatory to have all eggs graded by the standards set by Agriculture and Agri-Foods Canada (AAFC). The grade name appears on cartons. The grades Canada A and Canada B bear the maple leaf symbol with the grade name inside, and Canada C and Nest Run eggs will have the grade name printed in block text. The grades indicate the quality of the egg and should not be confused with size. Only Canada A are available in different sizes. The average large size egg weighs about 56 g (2 oz.) as indicated in Table 1.The Canada grade symbol does not guarantee that the eggs are of Canadian origin, but it does guarantee that the products meet Canadian government standards. Agriculture Canada inspects all egg-processing plants to ensure that the products are wholesome and processed according to sanitary standards. The pasteurization of “packaged” egg product is also monitored.The criteria for grading eggs are:Canada ACanada A eggs are clean, normal in shape with sound shells, and have the finest interior quality. They are ideal for all uses. The yolks are round and compact and surrounded by very thick, firm albumen. Canada A eggs are a premium quality and in limited supply on the retail market. If eggs are not sold within a limited time, unsold stocks are returned to the supplier. Eggs graded as A must meet the minimum weight for the declared size (see Table 12.) The size designation for Canada A eggs must appear on the label.Canada BCanada B eggs have very slight abnormalities. This grade is fine for baking, where appearance is not important. These eggs must weigh at least 49 g (1.75 oz.). There are no size designations on the label for Canada B eggs.Canada CCanada C is considered a processing grade and provides a safe outlet for the disposition of cracked eggs. Canada C eggs must be shipped to a federally registered processed egg station and pasteurized as a means of controlling the higher risk of salmonella or other microbial contamination that may be found in cracked eggs.These eggs are suitable for processing into commercially frozen, liquid, and dried egg products. Sizes are not specified.Canada Nest RunSince Canada Nest Run eggs are generally sent for further processing, they are usually not washed, candled (a process discussed later in this chapter), or sized. However, nest run eggs must meet the minimum quality requirements prescribed by the egg regulations. This grade, as with other Canada grades, can only be applied to eggs in a federally registered egg station.This page titled 7.1: Eggs Grade is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7.2: Composition and Nutrition

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Note: B-complex vitamins, not itemized, are well represented in eggs, as are amino acids. RE = retinol equivalent, a term used in nutritional measurement.Worth noting is the concentration of certain food elements in different parts of the egg. Note for example that all the cholesterol is in the yolk. The yolk is relatively rich in iron and the white is high in calcium.In practice, when separating large eggs, one estimates the weight of the white as 30 g (1 oz) and the yolk as 20 g (0.7 oz). The color of the shell, which is either a creamy white or brown, is relevant to the breed of the hen, and there is no other basic difference in the content of the egg or the shell.The color of the yolk depends on the diet of the hens. Bakers have a preference for eggs with dark yolks. Certainly the appearance of cakes made with such eggs is richer. Tests have found that, although eggs with darker yolks tend to produce moister sponge cakes, the cakes are somewhat coarser and less tender.This page titled 7.2: Composition and Nutrition is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7.3: Egg Products

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A number of egg products besides whole shell eggs are used in the baking and food service industry. By law, all egg products other than shell eggs are pasteurized to protect them against salmonella, and the low temperature at which they are kept inhibits bacterial activity, although under certain conditions they may spoil very rapidly.The chief categories of egg products available are:Liquid eggs (whole eggs and whole eggs with additional yolks) Frozen eggs (whole eggs, egg whites, and egg yolks) Dried and powdered eggs (whole eggs, egg whites, and meringue powder)Liquid and Frozen EggsLiquid and frozen whole eggs are preferred in large bakeries where cracking and emptying of shells is not economical. They are also one of the most economical ways of purchasing eggs. Liquid and frozen whole eggs are sometimes “fortified” by the addition of egg yolks. Some bakers feel that liquid or frozen eggs don’t yield the same volume in sponge cakes as fresh eggs, and there is a certain bias in favor of shell eggs.If stored in the freezer at -18°C (0°F) or lower, liquid and frozen eggs will keep for long periods with minimum loss of quality. Thawing should take place in the refrigerator or under cold water without submerging the container. Leaving frozen eggs at room temperature to thaw is a bad practice because the outside layers of egg can reach a temperature favorable to bacteria while the centre is still frozen. Heat should never be used to defrost eggs. Unused portions must be refrigerated and used within 24 hours.Frozen egg yolks consist of 90% egg yolks and 10% sugar to prevent the yolk from gelling and to avoid separation of the fat.Spray-Dried Whole Eggs and Egg WhitesDried eggs are used by some bakers as a convenience and cost saver. As with frozen eggs, some bakers doubt their performance in products such as sponge cakes. But dried eggs produce satisfactory results because of the addition of a carbohydrate to the egg before the drying process, usually corn syrup, which results in foaming comparable to fresh eggs.Dried whole eggs should be stored unopened in a cool place not over 10°C (50°F), preferably in the refrigerator. They are reconstituted by blending 1 kg (2.2 lb.) of powdered whole egg with 3 kg (6.6 lb) of cold water. The water is added slowly while mixing. Once reconstituted, dried eggs should be used immediately or refrigerated promptly and used within an hour.In mixes such as muffins and cake doughnuts, dried eggs can be mixed in with the other dry ingredients and do not have to be reconstituted. In layer cake formulas, dried eggs are blended with the other dry ingredients before the fat and some water are added, followed by the balance of liquid in two stages.Spray-dried egg whites are reconstituted by mixing 1 kg (2.2 lb.) of powdered egg white with 1 kg (2.2 lb.) of cold water, letting it stand for 15 minutes, and then adding 9 kg (20 lb.) of cold water. When used in cake mixes, the powdered egg white is blended with the other dry ingredients, but only 7 L (7 qt.) of cold water is used for every 1 kg (2.2 lb.) of powdered egg white. 221 Chemistry of CookingDry Egg Substitutes or ReplacementsEgg substitutes are made from sweet cheese, whey, egg whites, dextrose, modified tapioca starch, sodium caseinate, and artificial color and flavor. They are cost-cutters and can be used alone or in combination with fresh or dried eggs in cakes, cookies, and fillings. One kg (2.2 lb.) of powder is mixed with 4 kg (9 lb.) of water to replace powdered eggs.Meringue PowderWhile it is not a pure dehydrated egg white, meringue powder is widely used by bakers to make baked Alaska, royal icing, and toppings. It contains vegetable gums and starches to absorb moisture and make it whip better.This page titled 7.3: Egg Products is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7.4: The Function of Eggs

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Eggs are a truly multifunctional ingredient and have many roles to play in the bakeshop. Their versatility means that product formulas may be adjusted once the properties of eggs are understood. For example, in French butter cream, egg whites may be substituted in the summer for whole eggs to give a more stable and bacteria-free product (egg white is alkaline, with pH 8.5). A yolk or two may be worked into a sweet short paste dough to improve its extensibility. Sponge cake formulas can be adjusted, for example, with the addition of egg yolks in jelly rolls to improve rolling up.If a recipe is changed by replacing some or all of the eggs with water, two factors must be remembered:Water replacement is about 75% of the egg content, since egg solids constitute about 25% of the egg. Leavening ability is lessened and must be made up by the addition of chemical leavening.Other uses of eggs are:Leavening: They will support many times their own weight of other ingredients through their ability to form a cell structure either alone or in combination with flour. The egg white in particular is capable of forming a large mass of cells by building a fine protein network. Moistening and binding: The fat in eggs provides a moistening effect, and the proteins present coagulate when heated, binding ingredients together.Thickening: Eggs are valuable thickeners in the cooking of chiffon pie fillings and custard. Emulsifying: Lecithin, present in the yolk, is a natural emulsifier and assists in making smooth batters. Customer appeal: Eggs enhance the appearance of products through their colour and flavour, and they improve texture and grain.Structure: Eggs bind with other ingredients, primarily flour, creating the supporting structure for other ingredients. Shelf life: The shelf life of eggs is extended through the fat content of the yolk. Nutrition: Eggs are a valuable food in every respect. Note, however, that 4% of the lipid in egg yolk is cholesterol, which may be a concern to some people. Developments in poultry feed claim to have reduced or eliminated this cholesterol level.Tenderizing: The fat in eggs acts like a shortening and improves the tenderness of the baked cake.Keep these points in mind when using eggs:Spots in eggs are due to blood fragments in the ovary. Such eggs are edible and may be used. The albumen or egg white is soluble in cold water, congeals at 70°C (158°F), and remains insoluble from then on. Cover leftover yolks or whites tightly and refrigerate. Add a little water on top of yolks, or mix in 10% sugar, to prevent crusting. Do not return unused portions to the master container. Use clean utensils to dip egg products from their containers.This page titled 7.4: The Function of Eggs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7.5: Storing Eggs

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Whole eggs are the perfect medium for the development of bacteria and mould. Eggs with an undesirable odor may be high in bacteria or mould. While some of these odors disappear in baking, some will remain and give an off-taste to the product if the odor is concentrated and strong.Store fresh eggs in the refrigerator in cartons to prevent moisture loss and absorption of odours. If refrigerator space is at a premium, eggs are stable for up to three weeks if kept at a temperature of 13°C to 15°C (55°F to 60°F). Naturally, this must be in a location with invariable conditions.Food poisoning can result from using eggs held too long before using. Liquid or cracked eggs should be kept under refrigeration at all times.Whole eggs can be checked for freshness with the candling or salt water method:Candling method: Hold the egg up to a light in a darkened room or positioned so that the content or condition of the egg may be seen. If the yolk is held firmly by the white when the egg is turned, and the egg is clean and not broken, then the egg is of good quality. Smell or odor is not readily revealed unless the shell is broken.Salt water method: Add 100 g of salt to 1 L (3.5 oz. to 1 qt.) of water. Allow to dissolve completely. When an egg is placed in this mixture, its level of buoyancy determines the age of the egg. An old egg will float to the surface, while a fresher egg will sink to the bottom. This page titled 7.5: Storing Eggs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

8.1: From the Cocoa Bean to the Finished Chocolate

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In North America, chocolate manufacturing started in Massachusetts in 1765. Today, in the factory, the beans get cleaned, and magnets take out metallic parts, and then sand, dust, and other impurities are removed. Some starch will be changed into dextrins in the roasting process to improve flavor. Machines break the beans and grind them fine until a flowing liquid is produced, called chocolate liquor. Through hydraulic pressure, cocoa butter is reduced from 55% to approximately 10% to 24% or less, and the residue forms a solid mass called press cake.The press cake is then broken, pulverized, cooled, and sifted to produce commercial cocoa powder. The baking industry uses primarily cocoa powders with a low fat content.At the factory, chocolate is also subject to an additional refining step calcleodnching. Conching has a smoothing effect. The temperature range in this process is between 55°C and 65°C (131°F and 149°F). Sugar interacts with protein to form amino sugars, and the paste losesacids and moisture and becomes smoother.This video explains the chemical reactions related to heat, melting point, and formation of crystal structures in science360.gov/obj/video/27d9...stry-chocolateThis page titled 8.1: From the Cocoa Bean to the Finished Chocolate is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

8.2: Chocolate Produced for the Baking Industry

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True chocolate contains cocoa butter. Milk chocolate White chocolateUnsweetened ChocolateUnsweetened chocolate, also known as bitter chocolate, baking chocolate, or cooking chocolate, is pure cocoa liquor mixed with some form of fat to produce a solid substance. The pure ground, roasted cocoa beans impart a strong, deep chocolate flavor. With the addition of sugar in recipes, however, it is used as the base for cakes, brownies, confections, and cookies.Dark (Sweet, Semi-Sweet, Bittersweet) ChocolateDark chocolate has an ideal balance of cocoa liquor, cocoa butter, and sugar. Thus it has the attractive, rich color and flavor so typical of chocolate, and is also sweet enough to be palatable. It does not contain any milk solids. It can be eaten as is or used in baking. Its flavor does not get lost or overwhelmed, as in many cases when milk chocolate is used. It can be used for fillings, for which more flavorful chocolates with high cocoa percentages ranging from 60% to 99% are often used.Dark is synonymous with semi-sweet, and extra dark with bittersweet, although the ratio of cocoa butter to solids may vary.Sweet chocolate has more sugar, sometimes almost equal to cocoa liquor and butter amounts (45% to 55% range). Semi-sweet chocolate is frequently used for cooking. It is a dark chocolate with less sugar than sweet chocolate.Bittersweet chocolate has less sugar and more liquor than semi-sweet chocolate, but the two are often interchangeable when baking. Bittersweet and semi-sweet chocolates are sometimes referred to as couverture (see below). The higher the percentage of cocoa, the less sweet the chocolate is.Milk ChocolateMilk chocolate is solid chocolate made with milk, added in the form of milk powder. Milk chocolate contains a higher percentage of fat (the milk contributes to this) and the melting point is slightly lower. It is used mainly as a flavoring and in the production of candies and moulded pieces.White ChocolateThe main ingredient in white chocolate is sugar, closely followed by cocoa butter and milk powder. It has no cocoa liquor. It is used mainly as a flavoring in desserts, in the production of candies and, in chunk form in cookies.This page titled 8.2: Chocolate Produced for the Baking Industry is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

8.3: Couverture

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The usual term for top quality chocolate is couverture. Couverture chocolate is a very high-quality chocolate that contains extra cocoa butter. The higher percentage of cocoa butter, combined with proper tempering, gives the chocolate more sheen, firmer “snap” when broken, and a creamy mellow flavor. Dark, milk, and white chocolate can all be made as couvertures.The total percentage cited on many brands of chocolate is based on some combination of cocoa butter in relation to cocoa liquor. In order to be labelled as couverture by European Union regulations, the product must contain not less than 35% total dry cocoa solids, including not less than 31% cocoa butter and not less than 2.5% of dry non-fat cocoa solids. Couverture is used by professionals for dipping, coating, moulding, and garnishing.What the percentages don’t tell you is the proportion of cocoa butter to cocoa solids. You can, however, refer to the nutrition label or company information to find the amounts of each. All things being equal, the chocolate with the higher fat content will be the one with more cocoa butter, which contributes to both flavor and mouthfeel. This will also typically be the more expensive chocolate, because cocoa butter is more valuable than cocoa liquor.But keep in mind that just because two chocolates from different manufacturers have the same percentages, they are not necessarily equal. your recipe. Determining the amounts of cocoa butter and cocoa liquor will allow you to make informed decisions on chocolate choices.This page titled 8.3: Couverture is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

8.4: Definitions and Regulations (ADD US)

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The legislation for cocoa and chocolate products in Canada is found in Division 4 of the Food and Drug Regulations (FDR), under the Food and Drugs Act (FDA). The Canadian Food Inspection Agency (CFIA) is responsible for administering and enforcing the FDR and FDA. Here are some of the regulations governing cocoa and chocolate:The only sweetening agents permitted in chocolate in Canada are listed in Division 18 of the Food and Drug Regulations.Cocoa butter and sugar quantities are not defined in the regulations. Some semi-sweet chocolate may be sweeter than so-called sweet chocolate. And remember that bittersweet chocolate is not, as you might expect, sugarless. Only if the label states “unsweetened,” do you know that there is no sugar added.Products manufactured or imported into Canada that contain non-permitted ingredients (vegetable fats or oils, artificial sweeteners) cannot legally be called chocolate when sold in Canada. A non-standardized name such as “candy” must be used.Finally, lecithin, which is the most common emulsifying agent added to chocolate, is approved for use in chocolate in North America and Europe, but Canadian regulations state that no more than 1% can be added during the manufacturing process of chocolate. Emulsifiers like lecithin can help thin out melted chocolate so it flows evenly and smoothly. Because it is less expensive than cocoa butter at thinning chocolate, it can be used to help lower the cost. The lecithin used in chocolate is mainly derived from soy. Both GMO (genetically modified organism) and non-GMO soy lecithin are available. Check the manufacturer’s packaging and ingredient listing for the source of soy lecithin in your chocolate.This page titled 8.4: Definitions and Regulations (ADD US) is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.1: Elements of Taste

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Essentially there are a handful of elements that compose all of the taste profiles found in the foods we eat. Western definitions of taste conventionally define four major elements of taste:Asian cultures have added the following to the list:Foods and recipes that contain a number of these elements in balance are generally those that we think of as tasting good.This page titled 9.1: Elements of Taste is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.2: Introduction to Salt

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Historically, salt was a prestigious commodity. “The salt of the earth” describes an outstanding person. The word salary comes from the Latin salaria, which was the payment made to Roman soldiers for the purchase of salt. In Arabic, the phrase translated as “there is salt between us” expresses the covenant between humans and the divine. Though no longer a valuable commodity in the monetary sense, salt is still valuable in the sense of being crucial to human health. Common salt (sodium chloride) is 40% sodium and 60% chloride. An average adult consumes about 7 kg (15 lb.) per year.Salt can be found deposited in Earth’s layers in rock salt deposits. These deposits formed when the water in the oceans that covered Earth many millions of years ago evaporated. The salt was then covered by various types of rocks.Today, we have three basic methods of obtaining salt from natural sources:This page titled 9.2: Introduction to Salt is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.3: Origins of Salt

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In some countries, salt is mined from salt beds approximately 150 m to 300 m (490 ft. to 985 ft.) below Earth’s surface. Sometimes, impurities such as clay make it impossible to use rock salt without purification. Purification makes it possible to get the desired flavor and color, thus making it edible. Edible salt is highly refined: pure and snow white.Salt can also be mined from natural salt beds by using water to extract the salt in the form of a brine, which saves having to construct a mine. Holes are drilled approximately 20 cm (8 in.) in diameter until the salt deposits are reached. A pipe is then driven into the salt beds and another pipe is driven inside the larger pipe further into the deposits. Pressurized water is forced through the outer pipe into the salt beds, and then pumped back out through the smaller pipe to the refineries. Through separation of the impurities, eventually all water in the brine will evaporate, leaving crystallized salt, which then can be dried, sifted, and graded in different sizes.In some countries, especially those with dry and warm climates, salt is recovered straight from the ocean or salt lakes. The salt water is collected in large shallow ponds (also calledsalt gardens) where, through the heat of the sun, the water slowly evaporates. Moving the salt solution from one pond to another until the salt crystals become clear and the water has evaporated eliminates impurities. The salt is then purified, dried completely, crushed, sifted, and graded.This page titled 9.3: Origins of Salt is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.4: Functions of Salt in Baking

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Salt has three major functions in baking. It affects: Fermentation, Dough, and conditioning FlavorFermentation is salt’s major function: Salt has a binding or strengthening effect on gluten and thereby adds strength to any flour. The additional firmness imparted to the gluten by the salt enables it to hold the water and gas better, and allows the dough to expand without tearing. This influence becomes particularly important when soft water is used for dough mixing and where immature flour must be used. Under both conditions, incorporating a maximum amount of salt will help prevent soft and sticky dough. Although salt has no direct bleaching effect, its action results in a fine-grained loaf of superior texture. This combination of finer grain and thin cell walls gives the crumb of the loaf a whiter appearance.One of the important functions of salt is its ability to improve the taste and flavor of all the foods in which it is used. Salt is one ingredient that makes bread taste so good. Without salt in the dough batch, the resulting bread would be flat and insipid. The extra palatability brought about by the presence of salt is only partly due to the actual taste of the salt itself. Salt has the peculiar ability to intensify the flavor created in bread as a result of yeast action on the other ingredients in the loaf. It brings out the characteristic taste and flavor of bread and, indeed, of all foods. Improved palatability in turn promotes the digestibility of food, so it can be said that salt enhances the nutritive value of bakery products. The lack of salt or too much of it is the first thing noticed when tasting bread. In some bread 2% can produce a decidedly salty taste, while in others the same amount gives a good taste. The difference is often due to the mineralization of the water used in the dough.This page titled 9.4: Functions of Salt in Baking is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.5: Using Salt in Fermented Doughs

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The average amount of salt to use in dough is about 1.75% to 2.25% based on the flour used. Some authorities recommend that the amount of salt used should be based on the actual quantity of water used in making the dough, namely about 30 g per L (1 oz. per qt.) of water.During the hot summer months, many bakers find it advantageous to use slightly more salt than in the winter as a safeguard against the development of any undesirable changes in the dough fermentation. Salt should never be dissolved in the same water in which yeast is dissolved. It is an antiseptic and dehydrates yeast cells and can even kill part of them, which means that less power is in the dough and a longer fermentation is needed. In bread made by the sponge dough method and in liquid fermentation systems, a small amount of salt included in the first stage strengthens the gluten.This page titled 9.5: Using Salt in Fermented Doughs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.6: Storing Salt

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Salt is very stable and does not spoil under ordinary conditions. However, it may have a slight tendency to absorb moisture and become somewhat lumpy and hard. Therefore, it is advisable to store it in a clean, cool, and dry place. Inasmuch as salt can absorb odors, the storage room should be free from any odor that might be taken up and carried by the salt.This page titled 9.6: Storing Salt is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.7: Introduction to Spices and Other Flavorings

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Food touches all of the senses. We taste, we smell, we see color and shape, we feel texture and temperature, and we hear sounds as we eat. All of these elements together create a palette with an infinite number of combinations, but the underlying principles that make food taste good are unchanged.This page titled 9.7: Introduction to Spices and Other Flavorings is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.8: Seasoning and Flavoring

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Many ingredients are used to enhance the taste of foods. These ingredients can be used to provide both seasoning and flavoring.Knowing how to use seasonings and flavorings skillfully provides cooks and bakers with an arsenal with which they can create limitless flavor combinations. Flavoring and seasoning ingredients include wines, spirits, fruit zests, extracts, essences, and oils. However, the main seasoning and flavoring ingredients are classified as herbs and spices.Knowing the difference between herbs and spices is not as important as knowing how to use seasonings and flavorings skillfully. In general, fresh seasonings are added late in the cooking process while dry ones tend to be added earlier. It is good practice to under-season during the cooking process and then add more seasonings (particularly if you are using fresh ones) just before presentation. This is sometimes referred to as “layering.” When baking, it is difficult to add more seasoning at the end, so testing recipes to ensure the proper amount of spice is included is a critical process.This page titled 9.8: Seasoning and Flavoring is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.9: Herbs

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Herbs tend to be the leaves of fragrant plants that do not have a woody stem. Herbs are available fresh or dried, with fresh herbs having a more subtle flavor than dried. You need to add a larger quantity of fresh herbs (up to 50% more) than dry herbs to get the same desired flavor. Conversely, if a recipe calls for a certain amount of fresh herb, you would use about one-half of that amount of dry herb.The most common fresh herbs are basil, coriander, marjoram, oregano, parsley, rosemary, sage, tarragon, and thyme. Fresh herbs should have a clean, fresh fragrance and be free of wilted or brown leaves. They can be kept for about five days if sealed inside an airtight plastic bag. Fresh herbs are usually added near the completion of the cooking process so flavors are not lost due to heat exposure.Dried herbs lose their power rather quickly if not properly stored in airtight containers. They can last up to six months if properly stored. Dried herbs are usually added at the start of the cooking process as their flavor takes longer to develop than fresh herbs.This page titled 9.9: Herbs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.10: Spices

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Spices are aromatic substances obtained from the dried parts of plants such as the roots, shoots, fruits, bark, and leaves. They are sold as seeds, blends of spices, whole or ground spices, and seasonings. The aromatic substances that give a spice its particular aroma and flavor are the essential oils. The flavor of the essential oil or flavoring compound will vary depending on the quality and freshness of the spice.The aromas of ground spices are volatile. This means they lose their odor or flavoring when left exposed to the air for extended periods. They should be stored in sealed containers when not in use. Whole beans or unground seeds have a longer shelf life but should also be stored in sealed containers.Allspice is only one spice, yet it has a flavor resembling a blend of cloves, nutmeg, and cinnamon. dried in the sun. During drying they turn reddish-brown and become small berries. 0.6 cm (1/4 in.) in diameter and contain dark brown seeds.Allspice is grown principally in Jamaica and to a lesser degree in Mexico. Allspice is available whole or ground. Bakers usually use ground allspice in cakes, cookies, spices, and pies.Anise is the small, green-grey fruit or seed of a plant of the parsley family. The plant grows to a height of 45 cm (18 in.) and has fine leaves with clusters of small white flowers. It is native to Mexico and Spain, with the latter being the principal producer. Anise seeds are added to pastries, breads, cookies, and candies.Caraway is the dried fruit or seed of a biennial plant of the parsley family, harvested every second year, primarily in the Netherlands. It is also produced in Poland and Russia. herb grows up to 60 cm (24 in.) high and has small white flowers. Caraway is a small crescent-shaped brown seed with a pleasant aroma but somewhat sharp taste. Although it is most familiar in rye bread, caraway is also used in cookies and cakes.Native to India, Sri Lanka, and Guatemala, cardamom is the fruit or seed of a plant of the ginger family. The three-sided, creamy-white, flavorless pod holds the tiny aromatic, dark brown seeds. It is available in whole and ground (pod removed). Cardamom in ground form flavors Danish pastries and coffee cakes, Christmas baking, and Easter baking such as hot cross buns.Cinnamon comes from the bark of an aromatic evergreen tree. It is native to China, Indonesia, and Indochina. Cinnamon may be purchased in ground form or as cinnamon sticks. Ground cinnamon is used in pastries, breads, puddings, cakes, candy, and cookies. Cinnamon sticks are used for preserved fruits and flavoring puddings. Cinnamon sugar is made with approximately 50 g (2 oz.) of cinnamon to 1 kg (2.2 lb.) of granulated sugar.Cassia, sometimes known as Chinese cinnamon, is native to Assam and Myanmar. It is similar to cinnamon but a little darker with a sharper taste. It is considered better for savory rather than sweet foods. It is prized in Germany and some other countries as a flavor in chocolate.Cloves are the dried, unopened buds of a tropical evergreen tree, native to Indonesia. The flavor is characterized by a sweet, pungent spiciness. the ground version of this spice heightens the flavor of mincemeat, baked goods, fruit pies, and plum pudding.Ginger is one of the few spices that grow below the ground. It is native to southern Asia but is now imported from Jamaica, India, and Africa. The part of the ginger plant used is obtained from the root. Ground ginger is the most commonly used form in baking — in fruitcakes, cookies, fruit pies, and gingerbread. Candied ginger is used in pastries and confectionery.Originating in the East and West Indies, mace is the fleshy growth between the nutmeg shell and outer husk, yellow-orange in color. It is usually sold ground, but sometimes whole mace (blades of mace) is available. Mace is used in pound cakes, breads, puddings, and pastries.Nutmeg is the kernel or seed of the nutmeg fruit. The fruit is similar to the peach. The fleshy husk, grooved on one side, splits, releasing the deep-brown aromatic nutmeg. It is available whole or ground. Ground nutmeg is used extensively in custards, cream puddings, spice cakes, gingerbread, and doughnuts.Poppy seed comes from the Netherlands and Asia. they seem to be round. Poppy seeds are used in breads and rolls, cakes and cookies, and fillings for pastries.Sesame or benne seeds are the seeds of the fruit of a tropical annual herb grown in India, China, and Turkey. The seeds are tiny, shiny, and creamy-white with a rich almond-like flavor and aroma. Bakers use sesame seeds in breads, buns, coffee cakes, and cookies.The Spaniards named vanilla. The word derives from vaina, meaning pod. Vanilla is produced from an orchid-type plant native to Central America. The vanilla beans are cured by a complicated process, which helps explain the high cost of genuine vanilla. The cured pods should be black in color and packed in airtight boxes. Imitation vanilla extracts are made from a colorless crystalline synthetic compound called vanillin. Pure vanilla extract is superior to imitation vanilla. Artificial vanilla is more intense than real vanilla by a factor of 3 to 4 and must be used sparingly.To use vanilla beans, split the pod down the middle to scrape out the seeds. The seeds are the flavoring agents. Alternatively, the split pod can be simmered in the milk or cream used in dessert preparation. Its flavoring power is not spent in one cooking and it can be drained, kept frozen, and reused. A vanilla bean kept in a container of icing sugar imparts the flavor to the sugar, all ready for use in cookies and cakes.Vanilla extract is volatile at temperatures starting at 138°C (280°F) and is therefore not ideal for flat products such as cookies. It is suitable for cakes, where the interior temperature does not get so high.Vanilla beans and vanilla extract are used extensively by bakers to flavor a wide range of desserts and other items.This page titled 9.10: Spices is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9.11: Flavorings in Baking

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Flavors cannot be considered a truly basic ingredient in bakery products but are important in producing the most desirable products. Flavoring materials consist of:Note: Salt may also be classed as a flavoring material because it intensifies other flavors.These and others (such as chocolate) enable the baker to produce a wide variety of attractively flavored pastries, cakes, and other bakery products. Flavor extracts, essences, emulsions, and aromas are all solutions of flavor mixed with a solvent, often ethyl alcohol.The flavors used to make extracts and essences are the extracted essential oils from fruits, herbs, and vegetables, or an imitation of the same. Many fruit flavors are obtained from the natural parts (e.g., rind of lemons and oranges or the exterior fruit pulp of apricots and peaches). In some cases, artificial flavor is added to enhance the taste, and artificial coloring may be added for eye appeal. Both the Canadian and U.S. departments that regulate food restrict these and other additives. The flavors are sometimes encapsulated in corn syrup and emulsifiers. They may also be coated with gum to preserve the flavor compounds and give longer shelf life to the product. Some of the most popular essences are compounded from both natural and artificial sources. These essences have the true taste of the natural flavors.Aromas are flavors that have an oil extract base. They are usually much more expensive than alcoholic extracts, but purer and finer in their aromatic composition. Aromas are used for flavoring delicate creams, sauces, and ice creams.Emulsions are homogenized mixtures of aromatic oils and water plus a stabilizing agent (e.g., vegetable gum). Emulsions are more concentrated than extracts and are less susceptible to losing their flavor in the oven. They can therefore be used more sparingly.This page titled 9.11: Flavorings in Baking is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Sorangel Rodriguez-Velazquez via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

1: Fluids

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1.1: What is a Fluid?What is a fluid? Almost everything that we will discuss is soft matter under physiological temperature conditions: liquids and solutions, cytoplasm and cytosol, DNA and proteins in solution, membranes, micelles, colloids, gels... All of these materials can in some respect be considered a fluid.1.2: Radial Distribution FunctionThe radial distribution function, g(r), is the most useful measure of the “structure” of a fluid at molecular length scales. g(r) provides a statistical description of the local packing and particle density of the system, by describing the average distribution of particles around a central reference particle.1.3: Excluded VolumeOne of the key concepts that arises from a particulate description of matter is excluded volume. Even in the absence of attractive interactions, at short range the particles of the fluid collide and experience repulsive forces. These repulsive forces are a manifestation of excluded volume, the volume occupied by one particle that is not available to another. This excluded volume gives rise to the structure of solvation shells that is reflected in the short-range form of g(r) and W(r). This page titled 1: Fluids is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

InfoPage

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2: Lattice Model of a Fluid

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Concepts_in_Biophysical_Chemistry_(Tokmakoff)/01%3A_Water_and_Aqueous_Solutions/02%3A_Lattice_Model_of_a_Fluid

2.1: Lattice ModelsLattice models provide a minimalist, or coarse-grained, framework for describing the translational, rotational, and conformational degrees of freedom of molecules, and are particularly useful for problems in which entropy of mixing, configurational entropy, or excluded volume are key variables. The lattice forms a basis for enumerating different configurations of the system, or microstates. Each microstates may have a different energy, which is then used to calculate partition functions.2.2: Ideal Lattice GasThe description of a weakly interacting fluid, gas, solution, or mixture is dominated by the translational entropy or entropy of mixing. In this case, we are dealing with how molecules occupy a volume, which leads to a translational partition function.2.3: Binary Fluid This page titled 2: Lattice Model of a Fluid is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

4: Solvation

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4.1: SolvationSolvation describes the intermolecular interactions of a molecule or ion in solution with the surrounding solvent, which for our purposes will refer to water. Aqueous solvation influences an enormous range of problems in molecular biophysics, including charge transfer and charge stabilization; chemical and enzymatic reactivity; the hydrophobic effect; solubility, phase separation, and precipitation; binding affinity; self-assembly; and transport processes in water.4.2: Solvation ThermodynamicsLet’s consider the thermodynamics of an aqueous solvation problem. This will help identify various physical processes that occur in solvation, and identify limitations to this approach. Solvation is described as the change in free energy to take the solute from a reference state, commonly taken to be the isolated solute in vacuum, into dilute aqueous solution.4.3: Solvation Dynamics and Reorganization Energy This page titled 4: Solvation is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

5: Hydrophobicity

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5.1: Hydrophobic Solvation - ThermodynamicsThe hydrophobic effect refers to the free energy penalty that one pays to solvate a weakly interacting solute.5.2: Hydrophobic Solvation- Solute Size EffectTo create a new interface there are enthalpic and entropic penalties. The influence of each of these factors depends on the size of the solute (R) relative to the scale of hydrogen bonding structure in the liquid (correlation length, ℓ , ~0.5–1.0 nm).5.3: Hydrophobic Collapse This page titled 5: Hydrophobicity is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

6: Electrical Properties of Water and Aqueous Solutions

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6.1: Electrostatics6.2: Dielectric Constant and Screening6.3: Free Energy of Ions in Solution6.4: Ion Distributions in Electrolyte Solution6.5: Poisson–Boltzmann EquationThe Poisson–Boltzmann Equation (PBE) is used to evaluate charge distributions for ions around charged surfaces. It brings together the description of the electrostatic potential around a charged surface with the Boltzmann statistics for the thermal ion distribution.6.6: Debye–Hückel Theory6.7: Ion Distributions Near a Charged Interface6.8: Ion Distributions Near a Charged Sphere This page titled 6: Electrical Properties of Water and Aqueous Solutions is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

7: Statistical Description of Macromolecular Structure

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There are a number of ways in which macromolecular structure is described in biophysics, which vary in type of information they are trying to convey. Consider these two perspectives on macromolecular structure that represent opposing limits: atomistic vs. statistical. 7.1: Segment Models7.2: Excluded Volume Effects7.3: Polymer Loops This page titled 7: Statistical Description of Macromolecular Structure is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

8: Polymer Lattice Models

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Polymer lattice models refer to models that represent chain configurations through the placement of a chain of connected beads onto a lattice. These models are particularly useful for describing the configurational entropy of a polymer and excluded volume effects. However, one can also explicitly enumerate how energetic interactions between beads influences the probability of observing a particular configuration. At a higher level, models can be used to describe protein folding and DNA hybridization. 8.1: Entropy of Single Polymer Chain8.2: Self-Avoiding Walks8.3: Conformational Changes with Temperature8.4: Flory–Huggins Model of Polymer Solutions8.5: Polymer–Solvent Interactions ________________________________________1. K. Dill and S. Bromberg, Molecular Driving Forces: Statistical Thermodynamics in Biology, Chemistry, Physics, and Nanoscience. (Taylor & Francis Group, New York, 2010); S. F. Sun, Physical Chemistry of Macromolecules: Basic Principles and Issues, Array ed. (J. Wiley, Hoboken, N.J., 2004), Ch. 4.This page titled 8: Polymer Lattice Models is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

9: Macromolecular Mechanics

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An alternative approach to describing macromolecular conformation that applied both to equilibrium and non-equilibrium phenomena uses a mechanical description of the forces acting on the chain. Of course, forces are present everywhere in biology. Near equilibrium these exist as local fluctuating forces that induce thermally driven excursions from the free-energy minimum, and biological systems use non-equilibrium force generating processes derived from external energy sources (such as ATP) in numerous processes such as those in transport and signaling. For instance, the directed motion of molecular motors along actin and microtubules, or the allosteric transmembrane communication of a ligand binding event in GPCRs.Our focus in this section is on how externally applied forces influence macromolecular conformation, and the experiments that allow careful application and measurement of forces on single macromolecules. These are being performed to understand mechanical properties and stress/strain relationships. The can also be unique reporters of biological function involving the strained molecules.Remember \(k_BT\): 4.1 pN nm 9.1: Force and WorkHere we will focus on the stretching and extension behavior of macromolecules.9.2: Worm-like ChainThe worm-like chain is perhaps the most commonly encountered models of a polymer chain when describing the mechanics and the thermodynamics of macromolecules. This model describes the behavior of a thin flexible rod, and is particularly useful for describing stiff chains with weak curvature, such as double stranded DNA. Its behavior is only dependent on two parameters that describe the rod: its bending stiffness and its the contour length.9.3: Polymer Elasticity and Force–Extension Behavior This page titled 9: Macromolecular Mechanics is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

10: Diffusion

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10.1: Continuum DiffusionA significant fraction of how molecules move spatially in biophysics is described macroscopically by “diffusion” and microscopically through its counterpart “Brownian motion”. Diffusion refers to the phenomenon by which concentration and temperature gradients spontaneously disappear with time, and the properties of the system become spatially uniform. Brownian motion is also a spontaneous process observed in equilibrium and non-equilibrium systems.10.2: Solving the Diffusion Equation10.3: Steady-State Solutions This page titled 10: Diffusion is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

11: Brownian Motion

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Brownian motion refers to the random motions of small particles under thermal excitation in solution first described by Robert Brown,1 who with his microscope observed the random, jittery spatial motion of pollen grains in water. This phenomenon is intrinsically linked with diffusion. Diffusion is the macroscopic realization of the Brownian motion of molecules within concentration gradients. The theoretical basis for this relationship was described by Einstein in 1905,2 and Jean Perrin3 provided the detailed experiments that confirmed his predictions. Since the motion of any one particle is unique, the Brownian motion must be described statistically. We observe that the mean-squared displacement of a particle averaged over many measurements grows linearly with time, just as with diffusion.The proportionality factor between mean-squared displacement and time is the diffusion constant in Fick’s Second Law. As for diffusion, the proportionality factor depends on dimensionality. In 1D, if \(\langle x^2(t) \rangle /t = 2D \) then in 3D \( \langle r^2(t) \rangle /t = 6D \), where D is the diffusion constant. Brownian motion is a property of molecules at thermal equilibrium. It applies to a larger particle (i.e., a protein) experiencing an imbalance of many microscopic forces exerted by many much small molecules of the surroundings (i.e., water). The thermal agitation originates by partitioning the kinetic energy of the system on average as kBT/2 per degree of freedom. Free diffusion implies motion which is only limited by kinetic energy.Brownian motion applies to a specific range of forces and masses where thermal energy (kBT(300 K) = 4.1 pN nm) can have a significant influence on a particle. Let’s look at the average translational kinetic energy:\( \left< \dfrac{mv_x^2}{2} \right> = \dfrac{1}{2}k_BT \)For a ~10 kDa protein with mass ~10–23 kg, the root mean squared velocity due to thermal energy is \(v_{rms} = \langle v_x^2 \rangle^{1/2}\) = 20 m/s. For water at 300 K, D ~10–5 cm2/s. The same protein has a net displacement in one second of \(x_{rms}=\langle x^2 \rangle ^{1/2}=\sqrt{2Dt} \approx 50 \, \mu \text{m}\). The large difference in these values indicates the large number of randomizing collisions that this particle experiences during one second of evolution: (vrms\(\cdot\)1sec)/xrms ≈ 4×105. For the protein, the velocities and displacements are a dominant force on the molecular scale. In comparison, a 1 kg mass with kBT of energy will have vrms ~ 10–11 m/s, and an equally insignificant displacement!A system is known as ergodic when time average and ensemble averages for a time-dependent variable are equal.\[ \begin{aligned} \text{Ensemble average: } &\langle x \rangle = \dfrac{1}{N} \sum_i x_i = \int P(x)x \, dx \\ \text{Time-average: } &\overline{x(t)} = \lim_{T \rightarrow \infty} \dfrac{1}{T} \int^T_0 x(t) dt \end{aligned} \]In practice, the time average can be calculated using a single particle trajectory by averaging over the displacement observed for all time intervals within the trajectory such that t=(tfinal‒ tinitial).In the case of Brownian motion and diffusion: \( \left< |r(t) -r_0|^2 \right> = \overline{|r(t)-r_0|^2}\). 11.1: Random Walk and Diffusion11.2: Markov Chain and Stochastic Processes11.3: Fluorescence Correlation SpectroscopyFluorescence correlation spectroscopy (FCS) allows one to measure diffusive properties of fluorescent molecules, and is closely related to FRAP. Instead of measuring time-dependent concentration profiles and modeling the kinetics as continuum diffusion, FCS follows the steady state fluctuations in number density of a very dilute fluorescent probe molecule in the small volume observed in a confocal microscope.11.4: Orientational Diffusion ___________________________________This page titled 11: Brownian Motion is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

12: Diffusion in a Potential

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In this section, we extend the concepts of diffusion and Brownian motion into a regime where the time-evolution is not entirely random, but includes a driving force. We will refer to this class of problems as diffusion in a potential, although it is also referred to as diffusion with drift, diffusion in a velocity or force field, or diffusion in the presence of an external force. We will see that these problems can be related to a biased random walk or to motion of a Brownian particle subject to an internal or external potential. Our discussion below will be confined to problems involving diffusion in one dimension.The common theme is that we account for transport of particles through a surface in terms of two sources of flux, the diffusive flux and an additional driven contribution that arises from a potential, field, or external force experienced by the particle:\[J = J_{diff}+J_{U} \]Here we label the second flux component with U to signify potential. This may be a result of an external force acting on a diffusing system (for instance, electrophoresis and sedimentation), or the bias that results from interactions between diffusing particles. In mass transport through fluid flow the second term is known as the advective flux, JU → Jadv. 12.1: Diffusion with Drift12.2: Biased Random WalkThe diffusion with drift equation can be obtained from a biased random walk problem.12.3: Diffusion in a Potential This page titled 12: Diffusion in a Potential is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

13: Friction and the Langevin Equation

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Now let’s relate the phenomena of Brownian motion and diffusion to the concept of friction, i.e., the resistance to movement that the particle in the fluid experiences. These concepts were developed by Einstein in the case of microscopic motion under thermal excitation, and macroscopically by George Stokes who was the father of hydrodynamic theory. 13.1: Langevin Equation13.2: Brownian DynamicsThe Langevin equation for the motion of a Brownian particle can be modified to account for an additional external force, in addition to the drag force and random force. This page titled 13: Friction and the Langevin Equation is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

15: Passive Transport

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Passive transport is often synonymous with diffusion, where thermal energy is the only source of motion.\[ \langle r(t) \rangle = 0 \qquad \qquad \qquad \langle r^2(t) \rangle^{1/2}=\sqrt{6Dt} \qquad \qquad \qquad r_{rms}\propto \sqrt{t} \nonumber \]In biological systems, diffusive transport may work on a short scale, but it is not effective for long-range transport. Consider:\( \langle r^2 \rangle^{1/2} \) for small protein moving in water~10 nm →10–7 s~10 μm → 10–1 sActive transport refers to directed motion:\[ \langle r(t) \rangle = \langle v \rangle t \qquad \qquad \qquad \qquad r \propto t \nonumber \]This requires an input of energy into the system, however, we must still deal with random thermal fluctuations.How do you speed up transport?We will discuss these possibilities: 15.1: Dimensionality Reduction15.2: Facilitated DiffusionFacilitated diffusion is a type of dimensionality reduction that has been used to describe the motion of transcription factors and regulatory proteins looking for their binding target on DNA.15.3: Search Times in Facilitated Diffusion This page titled 15: Passive Transport is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

16: Targeted Diffusion

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16.1: Diffusion to CaptureIn this section we will discuss the kinetics of association of a diffusing particle with a target. What is the rate at which a diffusing molecule reaches its target? These diffusion-to-capture problems show up in many contexts.16.2: Diffusion to Capture with Interactions16.3: Mean First Passage Time This page titled 16: Targeted Diffusion is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

17: Directed and Active Transport

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17.1: Motor Proteins17.2: Passive vs Active Transport17.3: Brownian RatchetThe Brownian ratchet refers to a class of models for directed transport using Brownian motion that is rectified through the input of energy. For a diffusing particle, the energy is used to switch between two states that differ in their diffusive transport processes. This behavior results in biased diffusion. It is broadly applied for processive molecular motors stepping between discrete states, and it therefore particularly useful for understanding translational and rotational motor proteins.17.4: Polymerization Ratchet and Translocation Ratchet This page titled 17: Directed and Active Transport is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

18: Cooperativity

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It is often observed in molecular biology that nanoscale structures with sophisticated architectures assemble spontaneously, without the input of external energy. The behavior is therefore governed by physical principles that we can describe with thermodynamics and statistical mechanics. Examples include:Although each of these processes has distinct characteristics, they can be broadly described as self-assembly processes.A characteristic of self-assembly is that it appears thermodynamically and kinetically as a simple “two-state transition”, even if thousands of atomic degrees of freedom are involved. That is, as one changes thermodynamic control variables such as temperature, one experimentally observes an assembled state and a disassembled state, but rarely an intermediate, partially assembled state. Furthermore, small changes in these thermodynamic variables can lead to dramatic changes, i.e., melting of DNA or proteins over a few degrees. This binary or switch-like behavior is very different from the smoothly varying unfolding curves we derived for simple lattice models of polymers.Phase transitions and phase equilibria are related phenomena described by the presence (or coexistence) of two states. These manifest themselves as a large change in the macroscopic properties of the system with only small changes in temperature or other thermodynamic variables. Heating liquid water from 99 °C to 101 °C has a profound effect on the density, which a 2° change at 25 °C would not have.Such a “first-order” phase transition arises from a discontinuity in the free energy as a function of an intensive thermodynamic variable.1 The thermodynamic description of two-state behavior governing a phase transition is illustrated below for the equilibrium between phases A and B. The free-energy profile is plotted as a function of an order parameter, a variable that distinguishes the physical characteristics relevant to the change of phase. For instance for a liquid–gas-phase transition, the volume or density are order parameters that change dramatically. As the temperature is increased the free energy of each state, characterized by its free energy minimum (Gi), decreases smoothly and continuously. However, state B decreases more rapidly that state A. While state A is the global free-energy minimum at low temperatures, state B is at high temperature. The phases are at equilibrium with each other at the temperature where GA = GB.The presence of a phase transition is dependent on all molecules of the system changing state together, or cooperatively. In a first-order phase transition, this change is infinitely sharp or discontinuous, but the helix–coil transition and related cooperative phenomena can be continuous. Cooperativity is a term that can refer both to macroscopic phenomena and to a molecular scale. We use it to refer to many degrees of freedom changing concertedly. The size or number of particles or molecules participating in a cooperative process is the cooperative unit. In the case of a liquid–gas-phase transition, the cooperative unit is the macroscopic sample, whereas for protein folding it may involve most of the molecule.What underlies cooperativity? We find that the free energy of the system is not simply additive in the parts. The energy of a particular configurational state depends on the configuration of its neighbors. For instance, the presence of one contact or molecular interaction increases or decreases the propensity for a second contact or interaction. We refer to this as positive or negative cooperativity. Beyond self-assembly, cooperativity plays a role in the binding of multiple ligands and allostery. Here we want to discuss the basic concepts relevant to cooperativity and its relationship to two-state behavior.Based on observations we have previously made in other contexts, we can expect that cooperative behavior must involve competing thermodynamic effects. Structure is formed at the expense of a large loss of entropy, but the numerous favorable contacts that are formed lower the enthalpy even more. The free-energy change may be small, but this results from two opposing effects of large magnitude and opposite sign (H vs. TS). A small tweak in temperature can completely change the system. 18.1: Helix–Coil Transition18.2: Two-State Thermodynamics ________________________________________________1. A first order transition is described as a discontinuity in ∂G/∂S or ∂G/∂V. A second order transition is one in which two phases merge into one at a critical point and is described by a discontinuity in the heat capacity or expansivity/compressibility of the system (∂S/∂T, ∂S/∂P, ∂V/∂T, or ∂V/∂P).This page titled 18: Cooperativity is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

19: Self-Assembly

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Cooperative self-assembly refers to the the spontaneous formation of sophisticated structures from many molecular units. Generally, we think of this as involving many molecules (cooperative units), although single- and bi-molecular problems can be wrapped into this description, as in the helix–coil transition. Examples include:Although molecular structures also assemble with the input of energy, the emphasis here in on spontaneous self-assembly in the absence of external input. 19.1: Micelle FormationIn particular, we will focus on micellar structures formed from a single species of amphiphilic molecule in aqueous solution. These are typically lipids or surfactants that have a charged or polar head group linked to one or more long hydrocarbon chains.19.2: Classical Nucleation Theory19.3: Why Are Micelles Uniform in Size?19.4: Shape of Self-Assembled Amphiphiles This page titled 19: Self-Assembly is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

20: Protein Folding

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Many proteins spontaneously refold into native form in vitro with high fidelity and high speed. Different approaches to studying this phenomenon:Our emphasis here is mechanistic. What drives this process? The physical properties of the connected pendant chains interacting cooperatively give rise to the structure.It is said that the primary sequence dictates the three-dimensional structure, but this is not the whole story, and it emphasizes a certain perspective. Certainly we need water, and defined thermodynamic conditions in temperature, pH, and ionic strength. In a sense the protein is the framework and the solvent is the glue. Folded proteins may not be as structured from crystal structures, as one is led to believe.Kinetics and Dynamics Observed protein folding time scales span decades. Observations for protein folding typically measured in ms, seconds, and minutes. This is the time scale for activated folding across a free-energy barrier. The intrinsic time scale for the underlying diffusive processes that allow conformations to evolve and local contacts to be formed through free diffusion is ps to μs. The folding of small secondary structure happens on 0.1–1 μs for helices and ~1–10 μs for hairpins. The fastest folding mini-proteins (20–30 residues) is ~1 μs.CooperativityWhat drives this? Some hints:Levinthal’s paradox1The folded configuration cannot be found through a purely random search process.Two‐state thermodynamics To all appearances, the system (often) behaves as if there are only two thermodynamic states.Entropy/EnthalpyΔG is a delicate balance of two large opposing energy contributions ΔH and TΔS. Cooperativity underlies these observations Probability of forming one contact is higher if another contact is formed.Reprinted from K. A. Dill, K. M. Fiebig and H. S. Chan, Proc. Natl. Acad. Sci. U. S. A. 90,1942-1946. Copyright 1993 PNAS.Protein Folding Conceptual Pictures Traditional pictures rooted in classical thermodynamics and reaction kinetics.Framework/Kinetic Zipper Model Hydrophobic CollapseNucleation–CondensationNucleation of tertiary native contacts is important first step, and structure condenses around that.Some observations so far: ______________________________________________________ 20.1: Models for Simulating FoldingOur study of folding mechanism and the statistical mechanical relationship between structure and stability have been guided by models. Of these, simple reductionist models guided the conceptual development from the statistical mechanics side, since full atom simulations were initially intractable. We will focus on the simple models.20.2: Perspectives on Protein Folding Dynamics This page titled 20: Protein Folding is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

21: Binding and Association

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Molecular associations are at the heart of biological processes. Specific functional interactions are present at every level of cellular activity. Some of the most important:1)Proteins Interacting with Small Molecules and Ions2) Protein–Protein Interactions 3) Protein–Nucleic Acid InteractionsIn all of these examples, the common thread is a macromolecule, which typically executes a conformational change during the interaction process. Conformational flexibility and entropy changes during binding play an important role in describing these processes. 21.1: Thermodynamics and Biomolecular Reactions21.2: Statistical Thermodynamics of Biomolecular Reactions21.3: DNA Hybridization21.4: Biomolecular Kinetics21.5: Diffusion-Limited Reactions21.6: Protein Recognition and Binding21.7: Forces Guiding Binding21.8: Specificity in Recognition and Binding This page titled 21: Binding and Association is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

22: Biophysical Reaction Dynamics

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22.1: Concepts and Definitions22.2: Computing Dynamics22.3: Representations of DynamicsWe will survey different representation of time-dependent processes using examples from one-dimension.22.4: Analyzing Trajectories22.5: Time-Correlation Functions This page titled 22: Biophysical Reaction Dynamics is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

23: Barrier Crossing and Activated Processes

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Concepts_in_Biophysical_Chemistry_(Tokmakoff)/06%3A_Dynamics_and_Kinetics/23%3A_Barrier_Crossing_and_Activated_Processes

"Rare but important events"The rates of chemical reaction are obtained by calculating the forward flux of reactant molecules passing over the transition state, i.e. the time rate of change of concentration, population, or probability for reactants passing over the transition state.\[ \langle J^‡_f \rangle = dP^‡_R/dt \] ‡ 23.1: Transition State TheoryTransition state theory is an equilibrium formulation of chemical reaction rates that originally comes from classical gas-phase reaction kinetics.23.2: Kramers’ TheoryIn our treatment the motion of the reactant over the transition state was treated as a free transitional degree of freedom. This ballistic or inertial motion is not representative of dynamics in soft matter at room temperature. Kramers’ theory is the leading approach to describe diffusive barrier crossing. It accounts for friction and thermal agitation that reduce the fraction of successful barrier crossings. This page titled 23: Barrier Crossing and Activated Processes is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Andrei Tokmakoff via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.

InfoPage

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/00%3A_Front_Matter/02%3A_InfoPage

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1.3: Fermentation Paper

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.03%3A_Fermentation_Paper

You will write a research paper explaining the production of a fermented product not discussed in class or expanding on a covered topic. There must be significant chemistry/biochemistry in your paper. Additionally, there will be a comparison of the use or production in the US vs another country.Potential Topics for Review Article on Fermentation: • Meat preservation • Bletting of fruit (beyond ripening) • Olive Fermentation (effects on oleuropein) • Kimchee • Tempeh • Shalgam juice, hardaliye, or boza (Turkish fermented vegetable and grain beverages) • Injera (organisms, fermentation, and carbohydrates in t'eff) • Miso and Soy • Distilled alcoholic beverages • Impacts of Nitrogen/nutrients on fermentation in a specific product • Impacts of pH on fermentation in beer or wine • Effect of local water chemistry on brewing or distilling • Tannin and polyphenolics in beer production • Megasphaera cerevisiae effects on beer production (H2S formation) • Hop content on flavor profiles • Sulfur compounds in beers (production, regulation, flavor profiles) • 'Head' or foam on beers • Wheat ales • Barley wines • Cask conditioning of beers • Production of two short branched-chain fatty acids, 2-methylbutanoic acid and 3- methylbutanoic acid, imparting the “cheesy/sweaty” notes in many cheeses. • Propionic acid fermentation and the distinctive flavor of Swiss cheese • Mold Fermentations (e.g. • Microbe variability in flavors for a specific fermented product • Lactic Acid Bacteria and the undesirable flavor products in cider such as 'piqûre acroléique’ • Phenolic variation in wine varietals and flavor profiles • Impact of oxygen on wine (what happens to chemical profile after you open the bottle?) • Effects of chemical aging on wine • Champagne and sparkling wines • Wine (broad topic -- will need a narrower focus) • Tej: ethiopian honey wine • Sulfur compounds in wine (production, regulation, flavor profiles) • Champagne and sparkling wines • Malolactic fermentation in wine. This secondary fermentation process is standard for most red wine production and common for some white grape varieties such as Chardonnay, where it can impart a "buttery" flavor from diacetyl, a byproduct of the reaction. • Use of additives in wine. Ascorbic Acid, lysozyme, fumaric acid, sorbic acid, DMDC, tannins, gum arabic, colors. How do these impact chemistry and flavor? • Biological aging of wines. Sherry. Use of 'flor'. Chemical byproducts and pathways involved. • Astringency. Astringency is an important factor in the sensory perception of beers, ciders, and wines. • Tea • Chocolate • Coffee • Kombucha • Bulk chemical production • Pharmaceuticals • Wood-Ljungdal pathway for biofuel production • ABE fermentation • Enzymes needed for Gluten free bread • FODMAPs (fermentable oligosaccharides disaccharides, monosaccharides and, polyols) cause IBS and gluten sensitivity -- diets, solutions? • Microbe variability in flavors for a specific fermented product • Propose your own topicConfirm your topic for your research paper that includes these three key ideas: 1. Thesis statement (Purdue Online Writing Lab Tips for Writing a Thesis Statement) 2. 3. Cultural ComparisonWrite a 1-2 page outline of the literature on your topic. It should be in a typical bulleted or numbered form. See Purdue's Online Writing Lab for more details about writing an outline. This outline should contain an introduction and sufficient background biochemical pathway information, key experimental results, topics for discussion (applications/uses, variations), and a possible direction for cultural comparison essay.List in your bibliography at least 15 references, 10 of which must be primary references. For each reference, cite it in the appropriate format and write a 2-3 sentence summary of each reference.Complete the background and literature review of your fermentation topic. This section should cover the biochemical pathways involved in your topic. This should be a minimum of five pages. • Include drawings with structures (in ChemDraw) not clipped from a literature article.This section of the paper should address the applications or uses of your fermentation topic. It should be a complete story with current uses and modifications. This section of the paper should be at least 2-3 pages long.Some possible topics to cover: • What food or industrial applications are you exploring? • Why are people interested in this topic? • How is this technique or process or food used in US culture? • What are current concerns/problems with the process? • How are people attempting to improve this process? • Is climate change going to affect production? • Quality control issues? • Regulatory issues? • Are there different types of related fermentation products or processes?Outline or draft of the cultural comparison of your topic.This last section should be 2-3 pages that looks at cultural differences in either the production or process or use of your topic. This could include cultural differences in consumption or different regulatory processes or production. Compare and contrast differences between at least two countries or cultures. Please use citations to support your ideas.This is your final Fermentation Paper.There should be three parts:1. Literature Review (with edits incorporated). 2. Application Section (with edits incorporated). 3. Cultural comparison of your topic (with edits and insights from Amsterdam and Belgium incorporated).This page titled 1.3: Fermentation Paper is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.4: Basic Metabolic Pathways

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.04%3A_Basic_Metabolic_Pathways

This is just the beginning of energy production. NADH and FADH2 can be converted to more ATP. Oxidative phosphorylation is a metabolic pathway that transfers energy from NADH to the synthesis of ATP in the mitochondria.Electrons stored in the form of the reduced coenzymes, NADH or FADH2, are passed through a chain of proteins and coenzymes to reduce O2 – the terminal electron acceptor – into H2O.The energy released by electrons flowing through this electron transport chain is used to transport protons to generate a pH gradient across the membrane.Glucose is metabolized to produce energy (ATP) for the cell with the release of CO2 and H2O as byproducts. Glycolysis is a series of enzyme-catalyzed reactions that break glucose into 2 equivalents of pyruvate. This process (summarized below) is also called the Embden-Meyerhoff pathway.Assume all reactions take place within an enzyme. Glucose is first phosphorylated at the hydroxyl group on C6 by reaction with ATP.Glucose-6-phosphate is isomerized to fructose-6-phosphate in the next step. The glucose-fructose interconversion is a multistep process whose details are not yet fully understood.It begins with opening of the hemiacetal to an open-chain aldehyde.The open-chain aldehyde undergoes keto-enol tautomerization to the enediol which is further tautomerized to a different keto form.Cyclization of the open-chain hydroxy ketone gives fructose (hemiacetal).Fructose-6-phosphate is then converted to fructose 1,6-bisphosphate which is subsequently cleaved into two three-carbon compounds through a retro-aldol. Review: aldol reactionIf the reaction is driven to starting materials (retro-aldol), then the reaction will favor the starting materials.This mechanism is actually completed with an imine. Fructose 1,6-bisphosphate first reacts with the amino group of a lysine residue from an enzyme.The imine can then do a ‘retro-Stork enamine’ reaction (similar to the retro-aldol).Review: Stork Enamine (an adol with the enamine replacing the enolate anion as the nucleophile).If the reaction is driven to starting materials (retro-Stork enamine), then the reaction will favor the enamine and aldol starting materials.The products of the retro-Stork enamine are the enamine of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate (shown below).Glyceraldehyde 3-phosphate is oxidized and phosphorylated to 1,3-bisphosphoglycerate.Phosphoglycerate kinase catalyzes the transfer of a phosphoryl group from 1,3-bisphosphoglycerate to ADP forming ATP and 3-phosphoglycerate.3-phosphoglycerate is converted to phosphoenol pyruvate (PEP) through dehydration and dephosphorylation.In the last step of the metabolic breakdown of sugars (glycolysis), an enol phosphate is converted to pyruvic acid (shown below). The pyruvic acid is then converted to Acetyl Co A, which is the beginning of the TCA cycle.Hans Krebs and Fritz Lipmann shared the Nobel Prize for Physiology and Medicine in 1953 for their work on elucidating the Krebs cycle and coenzyme A. The Krebs Cycle [or tricarboxylic acid (TCA) or citric acid cycle] plays a central role in the metabolism of glucose to produce energy (ATP). The TCA cycle results ultimately in the oxidation of acetic acid to two molecules of carbon dioxide.Pyruvate (end product of glycolysis) must be converted to acetyl CoA to enter the TCA cycle. This process begins with the formation of a thiol ester from pyruvate.At this point, co-enzyme A reacts with the thiol ester (formed in question on previous page) to form acetyl CoA (shown below). To help keep track of the sulfurs, one is in a box and one is in a circle.In the next step Acetyl CoA reacts with oxaloacetate to form citryl CoA.Citryl CoA is then hydrolyzed to citrate.Citrate is converted to isocitrate through two steps.Isocitrate is oxidized to oxalosuccinate with NAD+.Ketoglutarate is transformed to succinyl CoA in a multistep process analogous to the transformation of pyruvate to acetyl CoA that we saw in the first step.Succinyl CoA is hydrolyzed to succinate and is coupled with the phosphorylation of guanosine diphosphate (GDP) to give guanosine triphosphate (GTP).Complex I is located in the inner mitochondrial membrane in eukaryotes. The electrons from NADH (produced in the TCA cycle) begin to be shuttled through small steps to capture the energy. This section will examine the mechanisms of electron transfer by the peripheral domain, proton transfer by the membrane domain and how their coupling can drive proton transport. The net reaction of Complex I is the oxidation of NADH and the reduction of ubiquinone. Net reaction: \[\ce{NADH + H^+ + UQ \rightarrow NAD^+ + UQH2}\]Complex II (aka succinate dehydrogenase from the TCA cycle) oxidizes succinate (–O2CCH2CH2CO2–) to fumarate (trans-–O2CCH=CHCO2–).Complex II also has a cascade of electron transfers. When succinate is converted to fumarate, the electrons are passed through a new cascade to eventually reduce UQ (just like Complex I!) \[\ce{succinate \rightarrow fumarate + 2H+ + 2e-}\] \[\ce{UQ + 2H+ + 2e- \rightarrow UQH2}\]Complex III (sometimes called cytochrome bc1 complex) has two main substrates: cytochrome c and UQH2. The structure of this complex was determined by Johann Deisenhofer (Nobel Prize for a photosynthetic reaction center – we will see this soon).This role of complex III is to transfer the electrons from UQH2 to cytochrome c.___ UQH2 + 1 UQ + 2 H+ + ___ cyt c+3 \(\ce{\rightarrow}\) ___ UQH2 + ___ UQ + 4 H+ + ___ cyt c+2 • There are two H+ coming from the mitochondrial matrix but _____ H+ are transported into the inter-membrane spaceAnother complex whose goal is to move electrons and protons! This is the big step since it is the main site for dioxygen utilization in all anaerobic organisms. The structure of complex IV is shown in the left figure and to the right in a diagram taken from the Kegg pathways (with permission).___ cyt c+2 + 1 O2 + 8 H+ \(\ce{\rightarrow}\) ___ H2O + 4 H+ + ___ cyt c+3Neglecting Complex II, the overall reaction of the mitochondrial chain, per 2e– transferred, can be written as: \[\ce{NADH + H+ + ½ O2 + 10 H+("in") \rightarrow NAD+ + H2O + 10 H+("out")} E° = +1.135V\]Each two e– (from 1 NADH molecule) through the electron transport chain results in the net transfer of 10 protons across the membrane: Protons will diffuse from an area of high proton concentration to an area of lower proton concentration. electrochemical concentration gradient of protons across a membrane could be harnessed to make ATP. The proton gradient created by the electron transport chain provides enough energy to synthesize about 2.5 molecules of ATP through a process called chemiosmosis.ATP synthase is an important enzyme that utilizes the proton gradient drive the synthesis of (ATP).Electric Potential Drives MotorThe rotor is not locked in a fixed position in the center of the bilayer and the rotor sites switch between the empty and the ion bound states. When driving ATP synthesis, an ion arrives from the periplasm and binds at an empty rotor site.The positive stator charge (Arg227) plays a fundamental role in the function of the F0 motor.During ATP synthesis, the ____________ gradient fuels the membrane-embedded F0 motor to rotate the central stalk. This rotation causes sequential binding changes at the peripheral F1 domain so that one catalytic site binds ________ and phosphate, the second makes tightly bound ATP, and the third step ____________.In anaerobically growing bacteria, when the respiratory enzymes are not active, the F1 motor can hydrolyze ATP.Dimroth, Operation of the F0 motor of the ATP synthase, Biochimica et Biophysica Acta (BBA) -Bioenergetics, 2000, 1458, 374-386.This page titled 1.4: Basic Metabolic Pathways is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.5: Intro to Microbial Metabolism

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.05%3A_Intro_to_Microbial_Metabolism

Oxygen (O2) is essential for organisms growing by aerobic respiration (previous worksheet). Many organisms are unable to carry out aerobic respiration because of one or more of the following circumstances:Fermentation usually refers to anaerobic processes in which organisms do not use molecular oxygen in respiration. Some microbes are facultative fermenters; they contain all the genes required to use either aerobic or anaerobic respiration pathways and they will use aerobic respiration unless there is no oxygen available. However, many prokaryotes are permanently incapable of respiration, even in the presence of oxygen because they lack enzymes or complexes to complete either TCA cycle or electron transport. These are obligate anaerobes.One important fermentation process is lactic acid fermentation. This process is common in lactobacilli bacteria (and many others). If respiration does not occur through oxidative phosphorylation, NADH must be re-oxidized to NAD+ for reuse in glycolysis through the EMP pathway (covered earlier).NAD+ is a catalyst in these reactions.Facultative microbes, particularly bacteria, often use pyruvate as a final electron acceptor.Lactic acid fermentation regenerates NAD+ but does not directly produce additional ATP.When lactic acid is the only fermentation product, the process is said to be homolactic fermentation; such is the case for Lactobacillus delbrueckii and S. thermophiles used in yogurt production.However, many bacteria perform heterolactic fermentation utilize the pentose phosphate pathway to produce a mixture of lactic acid and ethanol. More detail on this pathway follows. One important heterolactic fermenter is Leuconostoc mesenteroides, which is used for souring vegetables like cucumbers and cabbage, producing pickles and sauerkraut, respectively.The pentose phosphate pathway has three primary roles in metabolism (human and prokaryotic).There are two phases to these pathways: oxidative phase and non-oxidative phase.Ribulose-5-phosphate (the product of the oxidative stage) is the precursor to the sugar that makes up DNA and RNA.In the non-oxidative phase, there are different options that depend on the cell’s needs. The ribose-5-phosphate from step 3 is combined with another molecule of ribose-5-phosphate to make one, 10-carbon molecule. Excess ribose-5-phosphate, which may not be needed for nucleotide biosynthesis, is converted into other sugars that can be used by the cell for metabolism.Ribulose-5-phosphate (the product of the oxidative stage) is the precursor to the sugar that makes up DNA and RNA.Of interest for heterolactic fermentation, ribose-5-phosphate is converted to glyceraldehyde-3- phosphate which enters the glycolysis pathway to be converted to pyruvate and then lactic acid.The first step is a simple epimerization alpha to the carbonyl to convert ribose-5-phosphate to xylulose-5-phosphate.Propose a mechanism for this interconversion.The second step is a reaction of xylulose-5-phosphate with a ribose-5-phosphate to prepare a 7- carbon sugar and the glyceraldehyde-3-phosphate.Draw curved arrows for this mechanism.The glyceraldehyde-3-phosphate is then converted to lactic acid. This is a repeat of glycolysis and homolactic acid fermentation.Draw out the pathway to convert glyceraldehyde-3-phosphate to lactic acid.The next steps follow a similar pathway to produce other length sugars and more glyceraldehyde-3-phosphate.In heterolactive fermentation, xylulose-5-phosphate can also be converted directly to glyceraldehyde-3-phosphate and acetyl phosphate.Draw curved arrows for this mechanism.Acetyl phosphate can then be converted to ethanol. Suggest some steps for this conversion (HINT: Look at the ethanol fermentation pathway in yeast).Some bacteria often utilize the Entner-Doudoroff (ED) Glycolytic Pathway rather than the classic glycolysis pathway.du Toit, Englebrecht, Lerm, & Krieger-Weber, Lactobacillus: The Next Generation of Malolactic Acid Fermentation Starter Cultures, Food Bioprocess. Technol. 2011, 4, 876-906.This page titled 1.5: Intro to Microbial Metabolism is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.6: Vinegar and Acetic Acid Fermentation

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.06%3A_Acetic_Acid_Fermentation

The first description of microbial vinegar fermentation was made by Pasteur in 1862. He recognized that vinegar was produced by a living organism.Acetic acid bacteria (AAB), genus Acetobacter, are a group of Gram-negative bacteria which oxidize sugars or ethanol and produce acetic acid during fermentation. There are several different genera in the family Acetobacteraceae. AAB are found in sugary, alcoholic and acidic niches such as fruits, flowers and particularly fermented beverages. Given sufficient oxygen, these bacteria produce acetic acid (vinegar) from ethanol.Several species of acetic acid bacteria are used in industry for production of certain foods and chemicals. Commonly used feeds include apple cider, wine and fermented grain mashes. AAB are also involved in the production of other foods such as cocoa powder and kombucha. However, they can also be considered spoilage organisms.List 2-3 places/times that acetic acid bacteria would be considered spoilage organisms.AAB make acetic acid by two successive catalytic reactions of the alcohol dehydrogenase (ADH) and a membrane-bound aldehyde dehydrogenase (ALDH) that are bound to the periplasmic side of the cytoplasmic membrane.Ethanol, acetaldehyde, and acetic acid can be quite toxic for living organisms. However, AAB are able to live in both alcoholic and acid media because of a few adaptations.AAB are able to oxidize ethanol to acetic acid using a membranebound ADH and ALDH complexes with a PQQ cofactor.This enzyme is capable of oxidizing a few primary alcohols (C2 to C6) but not methanol or secondary alcohols.PQQ Reaction Mechanisms:Add a curved arrow mechanism for the oxidation of ethanol to acetaldehyde using this PQQ cofactor.How many electrons are transferred from the ethanol molecule to the PQQ in this step?In the second step, acetaldehyde forms a hydrate. Show the mechanism for this step.The acetaldehyde hydrate then reacts with another PQQ to form acetic acid. Propose a curved arrow mechanism for this transformation.The electrons are transferred electrons to ubiquinone (UQ) that are tightly linked to the respiratory chain (oxidative phosphorylation).Some Acetobacter and Gluconacetobacter strains can metabolize acetic acid to carbon dioxide and water using Krebs cycle enzymes. In vinegar, for instance, Acetobacter species exhibits a biphasic growth curve, where the first corresponds to an EtOH oxidation with AcOH production. The second spike in growth is due to ‘acetic acid assimilation’ wherein the bacteria move the ethanol and/or acetic acid into the cytoplasm to metabolize using the TCA cycle and oxidative phosphorylation.The overall chemical reaction facilitated by these bacteria is:\[\ce{C2H5OH + O2 → CH3COH → CH3COOH + H2O} \nonumber\]Propose a mechanism for the conversion of ethanol to acetaldehyde (reverse of the reduction done by yeast) utilizing NAD+.In the second step, acetaldehyde forms a hydrate which is then converted to acetic acid.Propose a mechanism for the conversion of acetaldehyde to acetic acid utilizing NAD+.In the third step, acetic acid is converted to acetyl CoA for use in the TCA Cycle.Propose the missing biological ‘reagents’ for this conversion.This page titled 1.6: Vinegar and Acetic Acid Fermentation is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.7: Carbohydrates

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.07%3A_Carbohydrates

Carbohydrates are the most abundant biomolecules on earth and are widely used by organisms for structural and energy-storage purposes. In particular, glucose is the most commonly used monosaccharide, thus, this is why all of the pathways that we have covered start with glucose.However, many microorganisms are able to utilize more complex carbohydrates for energy.Let’s look at the structures of different carbohydrates and their use in microbial metabolism.Monosaccarides are the building blocks (monomers) for the synthesis of polymers. These sugars are classified by the length of the chain and the position of the carbonyl.Glucose and Ribose are shown below.Glyderaldehyde and dihydroxyacetone are shown below.Monosaccharides of four or more carbon atoms are typically more stable when they adopt cyclic, or ring, structures. This is a nucleophilic addition the results in a hemiacetal.There hemiacetal formed when the sugar cyclizes is a new chiral center. Two possible orientations can be formed.Disaccharides are carbohydrates composed of two monosaccharide units that are joined by a carbon–oxygen-carbon linkage known as a glycosidic linkage.Three common disaccharides are the grain sugar maltose, made of two glucose molecules; the milk sugar lactose, made of a galactose and a glucose molecule; and the table sugar sucrose, made of a glucose and a fructose molecule.There are different types of glycosidic linkages. They are characterized by the numbering of the alcohols that are linked in the ether. And the anomer of the sugar.Thus, this is alpha-1,4-maltose.The human body is unable to metabolize maltose or any other disaccharide directly from the diet because the molecules are too large to pass through the cell membranes of the intestinal wall. Therefore, an ingested disaccharide must first be broken down by hydrolysis into its two constituent monosaccharide units. In the body, such hydrolysis reactions are catalyzed by enzymes such as maltase or lactase.** This will be important in upcoming discussions of beer, cheese, and yogurt production!Polysaccharides are very large polymers composed of hundreds to thousands of monosaccharides. These structures are used for energy storage or, in the case of cellulose, structural components. Starch is a mixture of two polysaccharides and is an important component of grains (wheat, rice, barley, etc.). This will again be important in bread and beer fermentations. These two polymers are amylose and amylopectin.Amylose is a straight chain polysaccharide (shown below).Amylopectin is a branched-chain polysaccharide. (cartoon shown below)Another Polysaccharide: CelluloseThis page titled 1.7: Carbohydrates is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.8: Fermented Vegetables

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.08%3A_Fermented_Vegetables

Vegetables may be preserved by fermentation or acidification. The most common commercial fermented vegetables include cucumbers, cabbage, and olives, but there are many other vegetables that have been used.Definitions:Typical Process for Vegetable Fermentation:Fresh cabbage contains about 4-8% fermentable sugars: glucose, fructose, and sucrose. Cucumbers have much lower amounts of these fermentable sugars.There are many complex polysaccharides in vegetables that are not fermentable or easily metabolized. This is often called fiber.Cellulose is a linear chain of thousands of linked D-glucose units.What type of linkages are used in this polysaccharide? Circle the correct designations.Pectin is a polysaccharide made from a mixture of monosaccharides. While many distinct polysaccharides have been identified and characterized within these ‘pectic polysaccharide family’, most contain stretches of linear chains of \(\alpha\)-(1–4)-linked D-galacturonic acid.Yeast and many microorganisms are usually present on surface of raw vegetables. Salt, either as a solid or as a brine solution, is added to the vegetable. Shredded cabbage or other suitable vegetables are placed in a jar. Salt, either as a solid or as a brine solution, is added to the vegetable so that is fully submerged. Mechanical pressure is applied to the cabbage to expel the juice, which contains fermentable sugars and other nutrients suitable for microbial activity.Salt, primarily NaCl, serves several major roles in the preservation of fermented vegetables:In addition, the salt can prevent the pectinolytic or cellulolytic enzymes from working.The fermentation of vegetables usually involves naturally occurring lactic acid bacteria (LAB). This is considered to be a wild fermentation as the LAB bacteria are found naturally on the vegetables. At the start, there are many bacteria that colonize the fresh vegetable; these organisms will compete. As the LAB begin to excrete lactic acid, the pH will decrease, and most other organisms will die.As the pH drops, the environment becomes too acidic for these bacteria to survive and they die out. In the second stage, Lactobacillus species that are better adapted to acidic environments will begin to flourish. Lactobacillus will continue to anaerobically ferment the remaining sugars into lactic acid until the pH reaches about 3.In sauerkraut, Leuconostoc mesenteroides converts the vegetable sugars, typically glucose, to lactic and acetic acids and carbon dioxide. Lc. mesenteroides also uses fructose as an electron acceptor, reducing it to mannitol. Fructose can be used as an electron acceptor being reduced to mannitol; this reaction contributes to the replenishment of the cells’ NAD+ pool.Given enough time, Lc. mesenteroides will continue to ferment mannitol to lactic acid.Sauerkraut consumption has decreased in the US. In taste comparisons of partially fermented European vs American sauerkraut vs fully fermented sauerkraut, most consumers preferred the flavors of the partially fermented European sauerkraut. The primary chemical differences were higher levels of remaining sugars, mannitol and ethanol (probably from post-processing addition of wine). Mannitol is sweet and has a desirable cooling effect often used to mask bitter tastes. However, ‘partially fermented’ sauerkraut can cause problems in bulk storage; remaining sugars allow spoilage organisms to thrive (and gas evolution). Fully fermented sauerkraut has no remaining sugars, so it does not need further processing.Many strains of Lc. mesenteroides and Lactobacillus can ferment malic acid (naturally found in vegetables) to lactic acid. The malolactic fermentation (MLF) involves the conversion of malic acid into lactic acid and carbon dioxide. Some LAB bacteria convert the malic acid in one step; while others utilize these steps that include intermediates from the TCA cycle.Sulfur aromas and flavors are strongly associated with cruciferous vegetables such as cabbage, radishes, kale, and broccoli. S-Methyl cysteine sulfoxide (SMCSO) naturally occurs in large quantities in fresh cabbage.Sauerkraut flavors are characterized mostly by salty, sour, and sulfur notes. The sulfur character of sauerkraut can lend both desirable flavors, as well as unfavorable aromas and flavors. This is often dependent upon concentration levels.Many of the compounds (shown below) found in sauerkraut are derived from the enzymatic degradation of SMCSO.DMTS and MMTSO2 appear to be the most critical compounds for the sauerkraut sulfur flavor.Caraway spiced commercial sauerkraut is known to be less sulfurous and milder in flavor than traditional sauerkraut, was found to contain no DMTS and the level of the DMDS was also lower. Caraway seeds appear to remove the precursor to these molecules, methanethiol.Spices, wines, and other ingredients may be added to the pickles to augment its flavor.After fermentation and removal from brine storage, cucumbers may be desalted or rinsed to reduce acid content.Many pickle and sauerkraut products undergo pasteurization in their glass containers before they are sold.Fleming HP, McFeeters RF. Residual sugars and fermentation products in raw and finished commercial sauerkraut In Sauerkraut Seminar, 1985, N. Y. State Agric. Expt. Sta. Special Report No. 56:25-29.Johanningsmeier, et. al. Chemical and Sensory Properties of Sauerkraut, J. Food Sci., 2005, 70, 343-349.Pérez-Díaz IM, Breidt F, Buescher RW, Arroyo-Lopez FN, Jimenez-Diaz R, Bautista-Gallego J, Garrido-Fernandez A, Yoon S, Johanningsmeier SD. 2014. Chapter 51: Fermented and Acidified Vegetables. In: Pouch Downes F, Ito KA, editors. Compendium of Methods for the Microbiological Examination of Foods, 5th Ed. American Public Health Association.This page titled 1.8: Fermented Vegetables is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.9: Cheese Production

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.09%3A_Cheese_Production

Cheese making is essentially a dehydration process in which milk casein, fat and minerals are concentrated 6 to 12-fold, depending on the variety. The basic steps common to most varieties are acidification, coagulation, dehydration, and salting.Cheese Production Process:Milk is primarily composed of water with four biological macromolecules; carbohydrate (lactose), fats, casein phosphoproteins, and whey protein.Caseins are phosphoproteins. These proteins are mostly random coils will little secondary or tertiary structure. They are highly heat stable.Casein exists in the milk as micelles that consist of hundreds of casein molecules coordinated with Ca+2 ions.Although the casein micelle is fairly stable, here are two major ways in which aggregation can be induced. Aggregation is a key step of cheese production.During the primary stage, rennet cleaves the Phe-Met linkage of kappa-casein forming a soluble protein which diffuses away from the micelle and para-kappa-casein.During the secondary stage, the micelles aggregate. This is due to the loss of steric repulsion of the kappa-casein. Calcium assists coagulation by acting as a bridge between micelles.During the tertiary stage of coagulation, a gel forms, the milk curd firms, and the liquid separates.2. Acid. Acidification causes the casein micelles to destabilize or aggregate. Acid coagulated fresh cheeses may include Cottage cheese, Quark, and Cream cheese.Acid coagulation can be achieved naturally with the starter culture of lactobacillus.Acid curd is more fragile than rennet curd due to the loss of calcium.Whey proteins include \(\beta\) -lactoglobulin, alpha-lactalbumin, bovine serum albumin (BSA), and immunoglobulins (Ig). These proteins have well defined tertiary and quaternary structures. They are soluble in water at lower pH but do not coagulate after proteolysis or acid treatment. When the casein is coagulated with enzymes or acid treatment, there is usually a straining step whereby the water is separated from the curd.There is a third process for casein coagulation, heat-acid.In this process, heat causes denaturation of the whey proteins which can interact with the caseins. With the addition of acid, the caseins precipitate with the whey proteins.In heat-acid coagulation, 90% of protein can be recovered. Examples of cheeses made by this method include Paneer, Ricotta and Queso Blanco.When lactobacilli are added to milk, the bacterium uses enzymes to produce energy (ATP) from lactose.The lactic acid curdles the milk that then separates to form curds, which are used to produce cheese and whey.We previously covered the pathway for bacteria to convert glucose to lactic acid.However, we haven’t talked about how this bacterium can convert lactose to glucose.Lactose is hydrolyzed to glucose and \(\beta\)-galactose.Glucose can be converted to lactic acid as discussed before. Galactose is converted into glucose 6-phosphate in four steps in the Leloir pathway.Leloir Pathway Stepwise1. The first reaction is the phosphorylation of galactose to galactose 1-phosphate.2. Galactose 1-phosphate reacts with uridine diphosphate glucose (UDP-glucose) to form UDP-galactose and glucose 1-phosphate are formed.3. The galactose moiety of UDP-galactose is then epimerized to glucose-1-phosphate. The configuration of the hydroxyl group at carbon 4 is inverted by UDP-galactose 4-epimerase. This enzyme utilizes NAD+ in the first step. And then regenerates the NAD+ in the second step.4. Glucose 1-phosphate, formed from galactose, is isomerized to glucose 6-phosphate by phosphoglucomutase.In this pathway, UDP-glucose and UDP-galactose fulfill catalytic roles but are not subject to any net turnover. It might therefore be said that they form a tiny metabolic cycle between the two of them.After the whey is removed the curds, there is a wide variety of curd handling dependent upon the type of cheese being prepared. Some cheese varieties, such as Colby or Gouda require a curd washing to increases the moisture content and reduce the acidity. Salt is added to some cheeses through different methods: Gouda is soaked in brine, while Feta has surface salt added.The curd is then ripened until the desired flavors and textures are produced. This ripening process includes further fermentation by bacteria, added yeasts or molds, and enzymatic reactions from added lipases or rennet. These processes develop distinctive characteristics for each cheese.The table below shows a sample of flavor molecules derived from the breakdown of milk components.More examples: Simon Cotton, Education in Chemistry, Royal Society of Chemistry, Really Cheesy ChemistryLipolysis is a critical step is the lipolysis of triglycerides to esters and acids which yield many flavorful molecules.Fatty acid metabolism (b-oxidation) removes to carbons at a time to each of these fatty acids.Esterases are often present that can turn these shorter chain fatty acids into methyl esters.These are smelly and flavorfulPropionibacterium species are facultative anaerobes that can ferment sugars (glucose or lactose) into propionic acid. This process creates aroma and flavors found in Swiss cheeses.A facultative anaerobe is an organism that: (choose the correct definition)This process hijacks a part of the TCA Cycle.A key step in the Wood-Werkman Pathway is to transfer a carboxyl group from methylmalonyl CoA to pyruvate to form propionyl CoA and oxaloacetate.This mechanism utilizes vitamin B12 (biotin).Draw the arrows for the decarboxylation of methylmalonyl CoA:Process continues with the carboxylated biotin and the enolate of pyruvate.Draw the enolate anion of pyruvate. Is this a nucleophile or an electrophile?As this step continues with the carboxylated biotin and the enolate of pyruvate to form oxaloacetate.Draw the arrows for this conversion.Now that you have made propionyl CoA. How is it converted to propionic acid?Draw arrows for this trans-thioesterification process. Be sure to include a tetrahedral intermediate.D. H. Hettinga and G. W. Reinbold, THE PROPIONIC-ACID BACTERIA–A REVIEW. Journal of Milk and Food Technology, 1972, 35, 358-372.This page titled 1.9: Cheese Production is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.10: Yeast Metabolism

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.10%3A_Yeast_Metabolism

Yeasts are ubiquitous unicellular fungi widespread in natural environments. Yeast have a broad set of carbon sources (e.g., polyols, alcohols, organic acids and amino acids) that they can metabolize but they prefer sugars. Yeast are capable of metabolizing hexoses (glucose, fructose, galactose or mannose) and disaccharides (maltose or sucrose) as well as compounds with two carbons (ethanol or acetate). The metabolic pathways utilized by yeast are Embden-Meyerhof glycolysis, tricarboxylic acid cycle (TCA), the pentose phosphate pathway, and oxidative phosphorylation.Embden-Meyerhof Glycolysis is the pathway utilized by most eukaryotes.Ethanol fermentation reaction occurs in two steps, decarboxylation and then hydride reduction.Show the curved arrows for this mechanism.2. The second reaction, catalyzed by the enzyme alcohol dehydrogenase, regenerates NAD+ by reducing the acetaldehyde to ethanol.Ethanol has the added benefit of being toxic to competing organisms. However, it will also start to kill the yeast that is producing the ethanol. at the accumulation of alcohol will become toxic when it reaches a concentration between 14-18%, thereby killing the yeast cellsEthanol fermentation utilizes the pyruvate from glycolysis to regenerate NAD+. This is an alternative pathway to metabolize glucose. The pathway is operated by Saccharomyces and other yeast fermenters that ultimately produces ethanol and CO2.When would you expect that an organism would choose to operate each pathway?Pasteur observed that yeast produce alcohol only as the product of a “starvation process” once they run out of oxygen. This observation has been shown to be incorrect!The Crabtree effect is the occurrence of alcoholic fermentation under aerobic conditions. The most common yeasts used in fermentation processes (Saccharomyces genus) will produce alcohol in both a beer wort and in bread dough immediately regardless of aeration. While you might expect the cell would perform aerobic respiration (full conversion of sugar and oxygen to carbon dioxide and water) as long as oxygen is present, while reverting to alcoholic fermentation, when there is no oxygen as it produces less energy.However, if a Saccharomyces yeast finds itself in a high sugar environment, it will immediately start producing ethanol, shunting sugar into the anaerobic respiration pathway while still running the aerobic process in parallel. This phenomenon is known as the Crabtree effect. People have speculated that yeast use the ability to produce ethanol to kill competing organisms in the high-sugar environment.Summarize:This page titled 1.10: Yeast Metabolism is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.11: Yogurt

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.11%3A_Yogurt

Yogurt has been around for several millennia. The mythological story about the discovery of yogurt suggests that sheepherders stored their milk in bags made of the intestinal gut of the animals. The intestines contain natural enzymes that cause the milk to curdle and sour. This soured milk lasted longer so they continued making it. Today, the FDA defines yogurt as a milk product fermented by two bacterial strains: a lactic acid producing bacteria: Lactobacillus bulgaricus and Streptococcus thermophiles.Yogurt Production Process:In step 4, yogurt cultures are added to milk. These bacteria are lactic acid fermenters; they use enzymes to produce energy (ATP) from lactose.Yogurt is often tart. This flavor is often attributed to the presence of lactic acid. However, there are also a number of carbonyl compounds like acetoin, diacetyl and acetaldehyde that also contribute to the tangy yogurt flavor.During yogurt fermentation, acetaldehyde could be produced from lactose metabolism as a result of pyruvate decarboxylation. However, the primary source of acetaldehyde in these bacteria is from the conversion of threonine (amino acid) into acetaldehyde and glycine.Many yogurt bacteria lack the enzyme, alcohol dehydrogenase.Both Streptococcus thermophilus and Lactobacillus bulgaricus produce diacetyl which provides a distinctive “buttery” flavor to yogurt (and other fermented milk products). Acetoin is the reduced form of diacetyl and it complements the diacetyl with a mild creamy flavor.Propose a mechanism.Yogurt cultures in the intestinal tract have been shown to release the enzyme lactase which continues to break down lactose in the dairy product. This makes yogurt edible for people who are lactose-intolerant.To give their products a longer shelf life, manufacturers often heat-treat yogurt after fermentation. This kills the live cultures. What will happen to lactase if the yogurt has been heat-treated after fermentation?Lactobacillus bulgaricus and Streptococcus thermophilus are the two main bacteria used for creating yogurt. However, these strains do not survive the gastrointestinal tract. They are destroyed by the acidity of the stomach and the enzymes of the pancreas. It has become common to add ‘probiotic’ bacterial strains to yogurt such as Lactobacillus acidophilus, Lactobacillus casei, or Bifidobacterium spp. There is evidence that these bacteria will make it to the intestine intact.When probiotics are added to foods, the food industry often also adds ingredients known as prebiotics, such as inulin, which will, after digestion, aid in the growth of the probiotics in the colon.Kefir is a carbonated fermented milk drink. The microbes involved in the production of kefir are a symbiotic culture of lactic acid bacteria and yeasts embedded in a matrix of proteins, lipids, and polysaccharides, ‘kefir grains’.Kefir Production Process:During the first fermentation, lactic acid bacteria are responsible for the conversion of the lactose present in milk into lactic acid, which results in a pH decrease and milk preservation.Similar to yogurt, the flavor of kefir is often attributed to diacetyl and acetoin (both of which contribute a "buttery" flavor), acetaldehyde, and related carbonyl products.Non-lactose fermenting yeast and acetic acid bacteria (AAB) also participate in the process. Propionibacteria further break down some of the lactic acid into propionic acid (these bacteria also carry out the same fermentation in Swiss cheese).Other kefir microbial constituents include lactose-fermenting yeasts such as Kluyveromyces marxianus, Kluyveromyces lactis, and Saccharomyces fragilis, as well as strains of yeast that do not metabolize lactose, including Saccharomyces cerevisiae, Torulaspora delbrueckii, and Kazachstania unispora.The lactose-fermenting yeast break the lactose down into ethanol and carbon dioxide resulting in a carbonated taste. Ethanol concentration is typically low, usually 0.2-0.3%.Review:Summarize:Zourari, Accolas, & Desmazeaud, Metabolism and Biochemical Characteristics of Yogurt Bacteria, A Review. Le Lait, INRA Editions, 1992, 72, pp.1-34. (Available in Canvas)This page titled 1.11: Yogurt is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.12: Bread

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.12%3A_Bread

Bread is a staple food in many cultures. The key ingredients are a grain starch, water, and a leavening agent. However, there are some breads without leavening agents (tortillas or naan), but these are flat breads.Typical Steps in Bread Production:Saccharomyces cerevisiae, also known as baker’s yeast, is the primary leavening agent in the production of most breads. Yeast cells consume the sugars present in dough and generate carbon dioxide (CO2) and ethanol that are responsible for dough leavening during the fermentation phase and the oven rise.Review:After flour, yeast and water are mixed, complex biochemical and biophysical processes begin, catalyzed by the wheat enzymes and by the yeast. These processes go on in the baking phase. The primary starches found in most cereal plants are the polymers amylose and amylopectin.Review:What are the monosaccharides in these polysaccharides? What are the linkages?These starches in the flour provide most of the sugar for fermentation, but the starch must be broken down into monosaccharides before it can be fermented by the yeast. Here is an overview of the sugars utilized by the yeast for the fermentation process:Amylases: Two types of amylases are present in wheat flour: \(\alpha\)-amylases and \(\beta\)-amylases.Yeast Invertase and MaltaseSometimes, \(\alpha\)-amylases are added to dough as part of a flour improver.Amongst the most important components of the flour are proteins, which often make up 10-15% of the flour. These include the classes of proteins called glutenins and gliadins. Gliadins are globular proteins with molecular weights ranging from 30,000 to 80,000 kDa. Gliadins contain intramolecular disulfide bonds.Glutenins consist of a heterogeneous mixture of linear polymers with a large molecular weight sections and low molecular weight branches (LMW). Disulfide bond cross-link the glutenin subunits.In the bread-making process, water is added to flour, where it hydrates the glutenin proteins, causing them to swell and become stretchy and flexible.Prior to kneading, the two main protein types, gliadin and glutanin, remain separate on a molecular level. However, as the dough is mixed and kneaded several things begin happening:The protease enzymes from the wheat begin to break the glutenin into smaller pieces.The glutenin and gliadin begin to form chemical crosslinks between the proteins. A complex network of proteins, gluten, is formed.Starch granules are trapped in the dough and air is incorporated into the dough during kneading. The dough needs to be elastic enough to relax when it rests and expand and hold CO2 when it rises — while still maintaining its shape.Eventually, the heat of the baking will kill the yeast.Fat and emulsifiers coat proteins.Salts (table salt, NaCl, or hard water salts such as Ca+2 or Mg+2 ) can strengthen the gluten network.Suggest how the presence of salts might strengthen gluten.Cookie: Usually quite crumbly and doesn’t rise very much.What would you need for a cookie dough?Pizza: To pull dough as thin as a pizza without breaking, there must be a very strong gluten network.What would you need for a pizza dough?Bread: A network is tight enough to trap the yeast’s CO2 allowing it to rise, but not so tight that it is free to expand.Exercise \(\PageIndex{11}\) • What would you need for a bread dough? o [ Low or Medium or High ] gluten formation o [ Low or Medium or High ] water contentBrewer’s Journal, Science/Maillard ReactionIn food chemistry, any heating steps involving the presence of sugars and amino compounds lead to a series of reactions called the Maillard reactions. These Maillard reactions are nonenzymatic ‘browning reactions’ that lead to the formation of a wide range of flavorful compounds which include; malty, toasted, bready and nutty flavors.There are three stages to the Maillard Reactions:Stage I: A condensation between the sugar and amine followed by the Amadori rearrangement. Stage III: Formation of heterocyclic nitrogen compounds.Tautomerizations can convert the Amadori Product to a dicarbonyl.The dicarbonyl reacts with an amino acid (asparagine in this example) to form an imine.In the Strecker degradation, the imine product undergoes a decarboxylation and is hydrolyzed to an aldehyde.• Complete the table with the Strecker aldehyde formed from these amino acids.In this stage, the Strecker aldehydes form complicated heterocycles in a variety of molecular families.furanones ‘sweet, caramel’pyrroles ‘nutty’Acylpryidines ‘cracker’furans ‘meaty, burnt’thiophenes ‘meaty,roasted’Alkylpryidines ‘bitter, burnt’pyranones ‘maple, warm, fruity’pyrazines ‘roasted, toasted’oxazoles ‘nutty, sweet’imidazoles ‘chocolate, bitter, nutty’The molecules can also form polymers and precipitates.This page titled 1.12: Bread is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.13: Beer

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.13%3A_Beer

Beer has been produced by humans for 6000 to 8000 years. The key ingredients are a malted barley, water, hops, and yeast.Typical Steps in Beer Production:Barley is a widely adaptable and hardy crop that can be produced in temperate and tropical areas. Barley kernels or grains are the fruit of the barley grass. The endosperm contains many starches as a food reserve for the baby plant. The starch and the embryo are surrounded by the husk, a protective layer around the kernel. While people have made beers from other grains, many people define beer as the fermented alcoholic barley drink. In fact, the German beer purity law, known as the Reinheitsgebot, of 1516 allows for only hops, barley, water and yeast in the production of beer.The goal of the first stage of beer making, malting the barley, is to access the fermentable carbohydrates.Review: Yeasts can utilize what sugars? What enzymes are used?The barley grains are soaked, called steeping. This process triggers metabolism in the grain to start germination for 4-5 days. As the baby plant starts to grow, the enzymes begin to break down the starches and the cell wall.The cell wall surrounding the starch containing endosperm is primarily made of \(\beta\)-glucan and pentosan.\(\beta\)-glucan and pentosan are structural polysaccharides that are NOT digestible by humans or yeast enzymes (i.e. fiber).Explain why germination is necessary for this step of the beer making process (or any food product that uses barley).To stop germination and enzymatic processes, the grain is heated, called kilning.There are many varieties of kilned malts. These are a few of the popular styles:Roasting the malts promotes Maillard reactions This leads to the complex flavors promoted during this stage.After kilning, the malt grain is then cleaned, transported, and stored. Most breweries purchase their malts rather than prepare them.A diastatic malt has enough enzymes (such as amylase) to convert the starch into fermentable sugars in the mashing stage.Brewing involves multiples steps. Here is an overview.There is some important chemistry occurring in these steps. We will look at some of the enzymes, the hops, and the boiling steps in more detail.In this step, the grains are broken up in a mill. The particle size, grist, can be determined by the spacing on the rotors.A large grist was traditionally favored because the crushed grain was used for the filtering at the end of the brewing process.Modern brewers use small grist because they use polypropylene filters.Mashing is the brewer's term for the hot water steeping process which hydrates the barley, activates the malt enzymes, and converts the grain starches into fermentable sugars.Typically, hot water is added to help solubilize starches.Hops are a climbing perennial vine and the cone of the flower is used to add ‘bittering’ and aroma flavors to the beer wort during this phase of beer production. Typically, these cones are milled and pressed into pellets for use by the brewer. Other brewers use extracts of the cones.The main components that hops adds to the beer are alpha acids (table 2) and resins (table 2).These alpha acids isomerize during the boiling process to produce iso-alpha acids (see below)The iso-alpha acids contribute the bitter flavor to most beers. It was also discovered that these compounds disrupt the proton pumps used by gram-positive bacteria.During the 1700s, the British Empire controlled India by maintaining a large army in India, they had a large demand for British brewed ales to be shipped to India. Unfortunately, many ales would spoil during the long sea journey. It was noticed that beers that were brewed at temperatures with higher concentrations hops were less likely to spoil – the beginning of the India Pale Ale (IPA) beers.‘Lightstruck beer’ or ‘skunk’ beer is one in which the iso-alpha acids have undergone a photochemical reaction to form MBT.Tannins are astringent polyphenolic compounds.Tannic Acid (example of a tannin):The tannin compounds are widely distributed in many species of plants, where they play a role in preventing predation. The astringent flavor predominates in unripe fruit, red wine or tea.Hops added after boiling is called ‘dry hopping’.Hop oils (essential oil) are sometimes added after boiling of the wort. These ‘aroma hops’ are volatile non-polar compounds that have strong aromas and flavors. There are between 400 and 1000 different compounds in hop oil including structures such as myrcene, humulene, caryophyllene, \(\beta\)-pinene, geraniol, linalool, and farnesene.There are several goals of boiling wort. Explain the importance of each of these steps:Liquid adjuncts (sugars/syrups) are usually added in the wort boiling stage. They may be sugars extracted from plants rich in fermentable sugars, notably sucrose from cane or beet or corn syrup. Liquid adjuncts are frequently called “wort extenders”.This is a filtering process that varies by brewer.There are hundreds of strains of yeast. Many beer yeasts are classified as "top-fermenting" type (Saccharomyces cerevisiae) and or "bottom-fermenting" (Saccharomyces uvarum, formerly known as Saccharomyces carlsbergensis). Today, as a result of recent reclassification, both yeast types are considered to be strains of S. cerevisiae.Ale yeast strains are best used at temperatures ranging from 10 to 25°C. These yeasts rise to the surface during fermentation, creating a very thick, rich yeast head. Fermentation by ale yeasts at these relatively warmer temperatures produces a beer high in esters, regarded as a distinctive characteristic of ale beers. These yeasts are used for brewing ales, porters, stouts, Altbier, Kölsch, and wheat beers.Lager yeast strains are best used at temperatures ranging from 7 to 15°C. At these temperatures, lager yeasts grow less rapidly than ale yeasts, and with less surface foam they tend to settle out to the bottom of the fermenter as fermentation nears completion. These yeasts are used in brewing Pilsners, Dortmunders, Märzen, Bocks, and American malt liquors.Beer that is brewed from natural/wild yeast and bacteria are called spontaneous fermented beers. One of the typical yeasts is the Brettanomyces lambicus strain which is used to produce traditional lambic beers. This brewing method has been practiced for decades in the West Flanders region of Belgium. We will visit 3 Fonteinen Brewery in Belgium that specializes in lambic beers.Longer chain alcohols produced by yeast during fermentation can also contribute to the aroma and flavor of beer. Primarily these alcohols can increase the warming of the mouthfeel.Fusel alcohols are derived from amino acid catabolism via a pathway that was first described by Ehrlich. Amino acids represent a major source of the assimilable nitrogen in the wort. Amino acids that are taken up by the yeasts and converted to fusel alcohols by the Ehrlich pathway (valine, leucine, isoleucine, methionine and phenylalanine).The Ehrlich pathway is shown below for phenylalanine.Too much of the higher weight fusel alcohols provides a harsh alcoholic taste (in fact, the word fusel is from the German for bad liquor).Fusel alcohols can be produced by excessive amounts of yeast or fermentation temperatures above 80°F.Fermentation Flavors: Ester ProductionMany of these esters are derived from alcohols reacting with acetyl coA.Some of the esters are derived from alcohols reacting with activated thioesters from the fatty acid synthesis pathway.Usually, brewers want a balance of esters present in the final product but not too many.While the presence of esters and fusel alcohols can enhance the flavor and aroma of beers, the presence of ketones is usually considered undesirable.The most common are the formation of diacetyl and acetoin. Diacetyl is most often described as a buttery flavor. It is desired in small quantities in many ales, but it can be unpleasant in larger quantities and in lagers; it may even take on rancid overtones.Diacetyl can be the result of the normal fermentation process or the result of a bacterial infection. Diacetyl is produced early in the fermentation cycle by the yeast and is gradually metabolized towards the end of the fermentation.Beer sometimes undergoes a "diacetyl rest", in which its temperature is raised slightly for two or three days after fermentation is complete.Beer style is a term used to differentiate and categorize beers by various factors, including appearance, flavor, ingredients, production method, history, or origin. There is no agreed upon method for distinguishing beer styles.There are some general categories that are used in describing beer styles:Yeasts: Ales vs LagersMalt types:Hops:Alcohol Content:Carbonation Level:Craft Beer.com provides a nice style guide on the different names of beers with information about the yeast strains, hop aroma, IBU (International Bitterness Units), alcohol content, carbonation for hundreds of beer styles.John Palmer also provides a nice table that places a wide range of beer styles on a chart comparing a number of ales and lagers on malty vs fruity and sweet vs bitter.Choose your favorite breweries or breweries chosen by your instructor.This page titled 1.13: Beer is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.14: Cider

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.14%3A_Cider

Cider is a drink made from apples. In the US, cider can refer to apple juice or the fermented, alcoholic version. This section will focus on the fermented, alcoholic drink.Typical Steps in Cider Production:Apples are the primary material used in cider production; thus, the final cider product quality and style depend heavily upon the quality of the apples used. Apples must be juicy, sweet, and ripened. A full-bodied cider requires the use of several different types of apples to give it a balanced flavor including a mix of sweet and tart apples.There are four main apple varietals. List them and their flavors.Apples are not peeled as the skin of the apples contains many of the compounds that contribute to the taste of the cider. The apples are ground and then pressed to extract the juice. The primary components of an apple are shown in Table 14.1. The fiber and insoluble carbohydrates are mostly removed in the pressing process.After pressing, the juice can be pasteurized and sold as apple juice or it can be further processed with fermentation to produce the alcoholic beverage.The primary sugars found in cider apple juice before fermentation are fructose, glucose, and sucrose.On a commercial scale, there are considerable cost advantages to supplementing the raw apple juice with glucose syrup and water as they are cheaper than apple juice. In fact, many commercial ciders are now made from around 35% juice and 65% glucose syrup.How would this impact the flavor?Pectin is a polysaccharide made from a mixture of monosaccharides. While many distinct polysaccharides have been identified and characterized within these ‘pectic polysaccharide family’, most contain stretches of linear chains of \(\alpha\)-(1–4)-linked D-galacturonic acid.Draw a linear chain of linear chains of \(\alpha\)-(1–4)-linked D-galacturonic acid.Most wild type yeasts cannot ferment galacturonic acid but failure to remove the pectin can lead to the formation of jelly during concentration. Thus, pectolytic enzymes are sometimes added prior to fermentation. This pectinase treatment often results in a release of higher concentrations of anthocyanins, tannins, and polyphenols from the apple pressings.How could the increased level of tannins and phenols impact the flavor of the final cider?Remaining pectin polysaccharides cause a haze in finished ciders, so pectinase is also sometimes added after fermentation to clear the cider.How would the presence of alcohol in the finished cider impact the effectiveness of the pectinase?French cider is often prepared with an initial step, ‘defecation’, in which pectins and other substances are separated from the juice using a gelatin. T hen, the clear juice is fermented slowly.These ciders are fruitier than others. Explain.Many cider makers add sulphur dioxide (or potassium metabisulphite) to inhibit the growth of most spoilage yeasts and bacteria, while permitting the desirable fermenting yeasts (such as Saccharomyces cerevisiae or uvarum) to facilitate the conversion to alcohol.Most natural weak acid preservatives (such as vinegar, benzoic acid or sorbic acid) are believed to work by diffusing through bacterial cell membranes. The increased acidity of the cytoplasm disrupts the cell homoeostasis and the cell has to work very hard to pump out protons to restore the pH. Eventually, the cells run out of ATP and die. Sulphite is believed to work in the same way as other weak acid preservatives.Apple juice (must) was traditionally fermented with the bacteria and yeast already present on the apples.The main yeasts found in wild fermentations is Saccharomyces bayanus. But Saccharomyces cerevisiae, Lachancea cidri, Dekkera anomala and Hanseniaspora valbyensis are also present is substantial amounts. Other species are present in small amounts: Candida oleophila, C. sake, C. stellate, C. tropicalis, H. uvarum, Kluyveromyces marxianus, Metschnikowia pulcherrima, Pichia delftensis, P. misumaiensis and P. nakasei.There are three phases in the cider process based on the dominant yeast species present.Fermentation should take 5 to 10 days, and up to 4 - 6 weeks at cool temperatures. Nearly all the sugar will then have been used by the yeast and the yeast will become dormant.Propose how cider-makers would determine when to stop fermentation.During alcoholic fermentation, many secondary metabolites are produced by the yeasts. Esters provide mainly fruity and floral notes; higher alcohols provide ‘background flavors’; whereas the phenolic compounds can generate interesting or unpleasant aromatic notes.Esters are the main volatile compounds in cider. They are characterized by a high presence of ethyl acetate, which alone can represent up to 90% of the total esters.Dioxanes, key flavor components of cider, are described as a ‘green, cidery’ flavor that results only from alcoholic fermentation of apples (and pears).These dioxanes are formed from reaction of acetaldehyde or other aldehydes (fermentation byproduct) with diols which are found almost exclusively in apples.Propose a mechanism for this reaction of acetaldehyde and octane-1, 3-diol.Another dioxane found in cider is formed from acetaldehyde and (R)-5(Z)-octene-1,3-diol.Draw the product found in cider.Racking is the process of moving the cider from its lees (the sediment formed).This is usually a filtration or centrifugation process.Pectinase may be added at this point.What is the purpose of this step?After racking, the cider maker may choose to do a secondary fermentation. Yeast might be added to ensure a sparkling cider, or a malolactic acid fermentation will be used to improve the flavor. (See next sections).Cider was traditionally stored in wooden barrels to age, but this is not essential if chilling and fining have been properly carried out after the fermentation.The bacteria needed for malolactic acid are often founded in the wood barrels.Cider fermentation with LAB bacteria convert the sugars and the malic acids into lactate. Malolactic fermentation is primarily completed by Leuconostoc oenos, a heterofermentative organism. This process tends to create a rounder mouthfeel to the final cider. Malic acid is typically associated with the taste of green apples, while lactic acid has a richer taste.The malolactic fermentation involves the conversion of malic acid into lactic acid and carbon dioxide. that include intermediates from the TCA cycle.Complete the steps in this biochemical pathway to convert malic acid to lactic acid.If malolactic fermentation is not fulfilling this function, then there must be some energy gain for the organism in completing this process.Secondary Fermentation: Malolactic Fermentation Energy and pHMLF process is shown. This reaction allows cells to regulate their internal pH.What happens to the overall H+ concentration inside the cell?This reaction allows cells to gain energy by creating a proton gradient across cell membranes. Some bacteria can utilize citrate or malate. The process allows out 1-2 proton atoms to be pumped out of the cell into the periplasm.Suggest a method for pumping out 2 H+ instead of 1 H+ in this process.The proton gradient created from MLF is coupled to an ATPase which captures the energy in the production of new ATP molecules.In cider production, this is important to reduce the malic acid content AND the overall raw acidic flavor of the cider.The proton pump will [ increase / decrease ] the acidity of the cider product (outside the cell).Depending upon the organism, these processes are inhibited with higher alcohol content and below pH of 3-4.If a cider producer wants to inhibit MLF in the cider, the pH of the must can be [ lowered / raised ] to prevent the process.Ciders are naturally ‘dry’. The term ‘dry’ means that there is little sweetness from remaining sugars, but more flavor from alcohol, fusel alcohols, esters, etc. Some consumers prefer a sweet still cider.Propose at least two methods for ensuring a sweet cider.To get some bubbles into cider, excess carbon dioxide under pressure can be added and then the cider is bottled or put in a keg which will withstand the pressure.Commercial cider-makers will sometimes inoculate with active dry yeast (Saccharomyces cerevisiae) before bottling to obtain a naturally-carbonated beverage.Because there is not much sugar left in the cider at this point, __________ is often added when using a second fermentation.This can be very successful although the bottom of each bottle will inevitably be a little cloudy when poured, because there will always be some yeast deposit which will be roused up when the pressure is released.Note: Bottles used for carbonated ciders must be designed to withstand the pressure generated by the gas!After all fermentation processes are complete, the must is either pasteurized or treated with ascorbic acid or sulfur dioxide.This step also decreases the chance of contamination by Acetobacter.This page titled 1.14: Cider is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.15: Wine

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.15%3A_Wine

Wine is defined as the fermented juice of a fruit. Wines have been produced from all kinds of plant materials and fruits. However, the most classic version is made from grapes.Typical Steps in Wine Production:The grape pulp has a high concentration of fermentable sugars while the skin and seeds have a lot of flavorful compounds.The grape is the fruit of the vine, Vitis vinifera (wine) and Vitis labrusca (table grapes). There are over 5000 varietals of grapes which all have different flavor and aroma profiles.A list of varietals (and pronunciations) is available from J. Henderson, Santa Rosa Junior College. The Wine Spectator has an article by J. Laube and J. Molesworth on Varietal Characteristics.In Europe, wines are usually categorized by their geographic region. In America, Australia, South Africa and New Zealand, wines are usually labelled by their varietal names.The grapes will develop a different profiles of flavor chemicals depending on soil, temperature, growing practices, rain, etc. The land and climate are referred to as the ‘terroir’.As grapes ripen on the vine, they accumulate sugars through the translocation of sucrose molecules that are produced by photosynthesis from the leaves. During ripening the sucrose molecules are hydrolyzed (separated) by the enzyme invertase into glucose and fructose.By the time of harvest, between 15 and 25% of the grape will be composed of monosaccharides; the total sugar content and the types will vary by cultivar.This includes glucose, fructose, and sucrose (fermentable sugars) and a small amount of sugars like the five-carbon arabinose, rhamnose and xylose.Sugars like arabinose have little flavor to humans and Saccharaomyces cannot metabolize them so they have little impact in wine unless Brettanomyces (wild yeast) or LAB are present.Organic Acids in Grapes: Tartaric, Malic, and Citric AcidsTartaric and malic make up over 90% of grape juice acid. Tartaric acid is rarely found in other fruits. There are some other organic acids present in small amounts including lactic, ascorbic (vitamin C), fumaric, pyruvic and more.The majority of the tartaric acid found in grapes is present as the potassium acid salt.Draw the potassium dipotassium salt of tartaric acid.In wine tasting, the term “acidity” refers to the fresh, tart and sour attributes of the wine which are evaluated in relation to how well the acidity balances out the sweetness and bitter components of the wine such as tannins.In the mouth, tartaric acid provides most of the tartness to the flavor of the wine, although citric and malic acids also play a role.To improve the flavor, the winemaker can add tartaric, malic, citric, or lactic to the grape juice (must).Polyphenols are a class of molecules characterized by the presence of large multiples of phenol structural units. This is a huge class of molecules found many plants. Grapes have a wide variety of polyphenols, most of which are concentrated in the skin and seeds.The concentration and types of polyphenols varies between grapes based on cultivar, ‘terroir’ – grape growing region (altitude, geological features, soil type, sunlight exposure), temperature during ripening, and environmental stressors such as heat, drought and light intensity.There are many sub-categories of polyphenols. Here is a simplified outline.The flavor and appearance of red wines are determined by the phenolic compounds: anthocyanins (responsible for the red color) and tannins (responsible for the sensation of astringency).Hydroxycinnamic Acids are mostly found in the grape pulp.Hydroxycinnamic acids are often found as esters of tartaric acid or with a sugar. During the processing, these esters are hydrolyzed.Hydroxybenzoates have been identified in both grapes and wines. These structures are the basis of hydrolysable tannins (next section)!Stilbenes have two aromatic rings connected with an alkene (cis or trans). Resveratrol is one of the most common stilbenes found in grapes and wine. It is usually located in the grape skin.Flavonoids are a class of compounds with a basic structure containing two aromatic rings bound through a three-carbon chain. Flavonoids are grouped into several classes (shown below). They can have many different substituents on the rings.Flavones, Flavanones, and Flavonols are mostly found in the seeds and skin.Many of these flavonoids are present in the grapes as the glycosides (the sugar moiety can also vary) but are cleaved in the processing to wine.Anthocyanins are also prevalent in wines and grapes. They are usually glycosylated. They are partially responsible for the color of grapes and wines.Tannins are polymeric forms of polyphenols.Most of the natural tannins present in grapes and wine are the ‘condensed type’, often dimers and trimers of polyphenols (flavonoid or non-flavonoid).Hydrolysable tannins are also present in grapes and wine. These are usually a sugar with several polyphenols covalently bound.Complex tannins are long polymeric mixtures of these structures.Harvesting of grapes is usually done in late summer and early fall. Harvesting for most large industrial wineries is mostly mechanical. The stems must be removed first to avoid ‘off-flavors’.The grades are crushed immediately after picking. The goal of crushing is to release the sugars, acids and some of the polyphenols from the skins. For white wines, the juice is separated from the skins so that the color and tannins are not extracted into the must. For red wines, the juice and skin are both fermented.The grape skin cell walls are composed of polysaccharides (pectins, hemicellulose and cellulose) that prevent the diffusion of polyphenols into the must.Excessive crushing can release too many polyphenols.Too sweet Too high alcohol Too low alcohol Too astringent Too dryDuring winemaking, phenolic compounds are extracted into the juice by diffusion. A diffusion period, ‘maceration’, can be done as a cold soak, through heating, enzymes, or a variety of techniques intended to increase polyphenol extraction. Maceration can be before, during, or after fermentation.Maceration enzymes (pectinases and cellulases) are often added during this process.Polyphenols are susceptible to oxidation with Fe and O2 in solution or through the action of some yeast enzymes.This oxidation is called browning because the quinones are a brown, muddy color.Winemakers will usually add SO2 to correct for the oxidation processes.Sulfite also prevents ethanol oxidation.It is important to remember that sulfite has another role; it can slow or prevent growth of spoilage organisms.This is a chart of some typical reactions that can occur to anthocyanins in the wine-making process including during fermentation including oxidation and condensations with yeast byproducts.These are just a few of the types of reactions that anthocyanins undergo during maceration and aging.Polymeric pigment formation increases progressively during maceration and aging ultimately leading to color changes, modification of mouthfeel properties, and, sometimes, precipitation.An important polymerization is the reaction of an anthocyanin with a flavanol (shown below).These large polymers start to precipitate and form a sediment.Sugar content is important as it effects the alcohol level of the final wine as well as the sweetness of the wine.‘Degrees Brix’ is a density measurement that represents the sugar concentration in wine.\[\text{1 degree Brix (°B) = (% by weight) = 1 gram of sugar per 100 grams solution (water & sugar combined)}\]Sucrose and/or grape juice can be added to the grape must.A wine with low acidity will taste "flat" whereas one with too high an acid level will be unpleasantly tart.Acid content is important for flavor and is important in some of the reactions involved in polyphenolic changes.Wine-makers will add tartaric, malic, citric, or lactic acids to adjust pH for the tartness of a wine. For most adjustments, tartaric acid is used because it disassociates best (lowers the pH more/gram).Fermentation of the ‘grape must’ is an alcoholic fermentation by yeasts.Wine-makers can utilize wild fermentation or inoculation with a specific yeast strains of Saccharomyces cerevisiae.In spontaneous wine fermentation, the fermentation begins with non-Saccharomyces yeasts until the ethanol concentration reaches 3–4%. As the alcohol concentration increases, these yeasts die off, and Saccharomyces dominates the fermentation process.In inoculated ferments, S. cerevisiae is used to begin the fermentation process and its primary role is to catalyze the rapid, complete and efficient conversion of grape sugars to ethanol.A good wine will have the components of alcohol, acidity, sweetness, fruitiness and tannin structure complement each other so that no single flavor overwhelms the others. Recently, there has been a demand for a ‘richer’ red wine flavor; this has led winemakers to harvest grapes at a later stage to obtain more polyphenols and flavors. However, more mature grapes have increased sugar concentration.In an attempt to develop full-bodied wines with lower alcohol content, researchers have been attempting to create strains of S. cerevisiae that produce glycerol instead of ethanol. Glycerol tastes slightly sweet with a slightly ‘oily’ mouthfeel but it does not dramatically change the overall sensory perception of the wine.Malic acid is described as a harsher or more aggressive acidic flavor. Wines with high levels of malic acid are submitted to malolactic fermentation (MLF). In general, winemakers use MLF to treat red wines more than whites. There are exceptions; oaked Chardonnay is often put through MLF.Malolactic Fermentation is described in detail in “Cider”.The bacteria behind this process can be found naturally in the winery, usually in the oak wine barrels used for aging. Alternatively, these bacteria can be introduced by the winemaker.The bacteria used in MLF are usually Pediococcus (homofermentative), Leuconostoc (heterofermentative, Oenococcus (heterofermentative) or Lactobacillus (either).Summarize MLF:The wine aging has two phases: 1) ‘maturation’, changes after fermentation and before 2) ‘bottling’. During the aging process, changes in taste and flavor occur.Traditional maturation involves the storage of wine in barrels for a few months to a few years (or even longer!). During this time, the wine undergoes reactions and absorbs compounds from the wood of the barrels.The polyphenolic component of the wine continues to undergo oxidations and polymerizations and condensations.The main phenolic compounds extracted from the wood to the wine during barrel ageing are hydrolysable tannins and phenolic acids.The volatile compounds extracted from wood are mainly furfural compounds, guaiacol, oak or whisky lactone, eugenol, vanillin, and syringaldehyde.As a wine ages, phenolic molecules combine to form tannin polymers that fall to the bottom of the bottle.Unlike beer and cider, filtration is not a common process for wines so many older wines will have sediment. Many winemakers leave the sediments in the wine bottle. Wine drinkers can ‘decant’ the wine before drinking – pour off the wine leaving behind the sediment.Fining is a technique that is used to remove unwanted juice/wine components that affect flavor and aroma.Bentonite is a clay made of soft silicate mineral that will absorb positively charged proteins that cause hazing of wines (particularly white wines).Bovine Serine Albumin (BSA) or gelatin or casein are added to bind with excess tannins and precipitate out of the wine.Filtration is sometimes used to help control both MLF and Acetic Acid bacteria and other spoilage organisms since lees are a food source for the bacteria. LAB can continue the fermentation leading to off-flavors. Membrane filtration can be helpful at this point to remove organisms.The flavor and aroma components, including polyphenols, acids, aldehydes, esters, and fusel alcohols are a very small percentage of the overall beverage.A dry wine has little residual sugars, so it isn't sweet. Sugars are the main source of perceived sweetness in wine, and they come in many forms.While it seems paradoxical, many people have noticed that wines with higher sugar content last longer even when open to the air.Osmotic pressure seems to play a part: high concentrations of sugar force the water within a microbe to rush outward, and its cell walls collapse.Sweetness from Aging ProcessesIn 2017, scientists in Bordeaux discovered a set of molecules called quercotriterpenosides, which are released from oak during aging. These molecules are small but mighty, influencing the taste of wine at even low doses due to their extreme sweetness.Other oak flavors can evoke sweetness: guaiacol, eugenol, and vanillin.Glycerol can also provide a sweet sensation.Aroma and flavors: Esters and alcoholsDuring alcoholic fermentation, many secondary metabolites are produced by yeast. Esters provide mainly fruity and floral notes; higher alcohols provide ‘background flavors’; whereas the phenolic compounds can generate interesting or unpleasant aromatic notes.Esters are the main volatile compounds in cider. They are characterized by a high presence of ethyl acetate, which alone can represent up to 90% of the total esters.Esters and Fusel Alcohols were covered in the ‘Beer’ Section.Too many esters or fusel alcohols are considered a fault in wines.Acetic acid is responsible for the sour taste of vinegar. During fermentation, activity by yeast cells naturally produces a small amount of acetic acid.If the wine is exposed to oxygen, Acetobacter bacteria will convert the ethanol into acetic acid and is considered a fault.The process for ‘acetification’ (conversion of ethanol to acetic acid by AAB is covered in the ‘Vinegar’ section.Lactobacilli and contaminant yeasts like Brettanomyces are often present during wine-making.These organisms are often responsible for ‘taints’, unpleasant chemical flavors.A common taint is the production of volatile phenols, compounds are derived from the naturally occurring hydroxycinnamic acids in grapes/wine.Humans can taste volatile phenols at very low concentrations and can have a strong influence on wine aroma. These compounds are described as medicinal, animal, leather and ‘horse sweat’ odors.Bitterness taint is produced by LAB. The bacteria degrade glycerol, a compound naturally found in wine, to 3-hydroxypropionaldehyde. During aging, this is converted to acrolein which reacts with the anthocyanins and other phenols present within the wine.Mannitol is often described as an ester flavor with a sweet and irritating aftertaste. This was covered in the Cider section.Draw the pathways for the production of mannitol.Diacetyl in wine is produced by lactic acid bacteria. This compound has an intense buttery flavor.This was covered in the Beer section.Draw the pathways for the production of diacetyl.Potassium sorbate is sometimes added to wine as a preservative against yeast. However, LAB will metabolize the sorbic acid into 2-ethoxyhexa-3,5-diene which provides a flavor reminiscent of geranium leaves.Mousiness is a wine fault that can occur during MLF. The compounds responsible are lysine derivatives. The taints are not volatile but, when mixed with saliva in the mouth, they provide a flavor of mouse urine.Certain species of Leuconostoc have been found to produce dextran slime or mucilaginous substances in wine.Belda, et. al., Microbial Contribution to Wine Aroma, Molecules 2017, 22, 189Casassa, Flavonoid Phenolics in Red Winemaking In Grapes and Wine, A. M. Jordão, Ed., 2018, InTechOpen.Chantal Ghanam, Study of the Impact of Oenological Processes on the Phenolic Composition of Wines, Thesis, Université de Toulouse.Dangles & Fenger, The Chemical Reactivity of Anthocyanins, Molecules, 2018, 23, 1970-1993.Danilewicz, Role of Tartaric and Malic Acids in Wine Oxidation, J. Agric. Food Chem. 2014, 62, 22, 5149-5155.du Toit & Pretorius, Microbial Spoilage, S. Afr. J. Enol. Vitic. 2000, 21, 74-96.E.J. Bartowsky, Bacterial Spoilage of Wine, Letters in Applied Microbiology, 2009, 48, 149–156.Garrido & Borges, Wine and Grape Polyphenols, Food Research International, 2013, 54, 1844–1858Goold, et. al. Yeast's balancing act between ethanol and glycerol production in low-alcohol wines, Microbial Biotechnology 2017, 10, 1-15.He, et. al., Anthocyanins and Their Variation in Red Wines, Molecules, 2012, 17, 1483-1519.J. Harbertson, A Guide to the Fining of Wine, Washington State UniversityLi, Guo, & Wang, Mechanisms of Oxidative Browning of Wine, Food Chemistry, 2008, 108, 1-13.Marchal, et. al. Identification of New Natural Sweet Compounds in Wine, Anal. Chem, 2011, 83, 9629-9637.Niculescu, Paun, and Ionete, The Evolution of Polyphenols from Must to Wine, In Grapes and Wine, A. M. Jordão, Ed., 2018, InTechOpen.This page titled 1.15: Wine is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

1.16: Distilled Spirits

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Fermentation_in_Food_Chemistry/01%3A_Modules/1.16%3A_Distilled_Spirits

Distilled spirits are all alcoholic beverages in which the concentration of ethanol has been increased above that of the original fermented mixture by a method called distillation. More Information about Distilling: Artisanal Distilling, A Guide for Small Distilleries, Kris BerglundDistilled Spirits Production Steps:Any sugar containing fruit or syrup can be used for fermentation and then distilled to prepare spirits. Similarly, grains and potatoes are fermentable and can be used for whiskey or vodka production. Like wine and cider production, the fruits are harvested and mashed to release enzymes and simple mono- and di-saccharides.Review: Describe the steps and any necessary additives (like pectinases and sulfite)For grain spirits, the process involves malting of the grain, milling, boiling a mash to release the complex carbohydrates.Review: Describe the steps and any necessary additives (like amylases)As you remember from the ‘Cider’ unit, many fruits contain a large amount of pectin. Pectin is a polymer of the sugar galacturonic acid.This pectin can form a gel that is undesirable in ciders or fruit beverages, so it is necessary to allow native pectolytic enzymes to hydrolyze this polysaccharide. In addition, some producers add extra pectolytic enzymes. Pectin methylesterase is an enzyme found in cherries, pears, and apples that hydrolyzes the esters that are on the side chains of pectin.Show the product of this reaction.In cider or wines, the small amounts of methanol formed in this process are not a concern. However, when the wine is distilled the methanol is also concentrated and can have toxic impacts on consumers. One way to limit the formation of methanol is by heating of the mash to a temperature of 80- 85 °C.What will this do to the enzyme?Fermentation is the same process as seen in the previous discussions of Bread, Beer, Cider, and Wine.5% 10% 15% 20% 25% 30% 35% 45% 50% 60% 75%Distillation in the concentration of ethanol content in an alcoholic beverage through boiling. Ethanol boils at a lower temperature ( 78.4 °C or 173.12 °F) than water ( 100 °C or 212 °F). When the fermentation mixture is heated, the ethanol is evaporated in a higher concentration in the steam. This is condensed and collected resulting in a product that is approximately 25- 35% alcohol.If a distillery desires a higher concentration of alcohol, then what will they need to do?The still vessel is filled with mash, wine, or beer up to 50-75 % full and then closed. More viscous mashes are diluted with 20 % water. Pomaces which yield a low alcohol content are mixed preferentially with 20 % coarse spirit.Most distilleries use copper stills as they produce cleaner and aromatic because copper reacts with the sulfur side-products found in mashes to form non-volatile compounds.What is the problem with sulfur side-products in mash (and then the final product)?Boiling points of different alcohols present in mashes:Most distillers will collect three fractions from the distillation process: fore-run (head), middlerun (heart), and after-run (tail).What is the primary component(s) in each fraction?Which fraction will be sold as a distilled spirit?With direct heating of the fermentation product in the pot stills, the highly viscous mashes/fruit pulps can lead to burning.The decomposition products of sugar leads to ___________________. The products formed in this process can lend a bitter or burnt flavor to the final distilled spirits.Wood fires directly below the pot are problematic due to leads to concerns about burning the mash and possible explosions.Why is distillation prone to fires? Hint: consider flammability of the product.Some whisky distillers choose to use the wood fired heating because they like the flavors. To keep the mash from burning, they use a ‘rummager’ to continuously stir the mash. The fire also requires careful tending, making sure it’s not burning too hot or too cold. To prevent burning the mash, other distillers have moved to steam, hot water baths around the pot, or electrical heating.With column distillation, the mash enters near the top of the still and begins flowing downward. This brings it closer to the heating source, and once it’s heated enough to evaporate, the vapor rises up through a series of partitions known as plates or stripping plates. At each plate along the way, the vapor ends up leaving behind some of the higher boiling compounds. It is important to note that pot stills operate on a batch by batch basis, while column stills may be operated continuously allowing higher throughput.Is scorching a problem with this method?The aging process is similar to wines. The aging process allows tannins, terpenes, lignins, polyphenols, and minerals from the wood of the barrel to dissolve into the spirits. Many of the barrels have been charred so there are oxidized lignin and wood sugars also available. As these compounds are dissolved into the spirits, new condensation and oxidation reactions can occur during this process.Some barrels have been previously used for wines so they will also release flavors from the polyphenols of wines that were absorbed into the wood.Each of the distilled spirits have a slightly different aging process.You will notice that the more northern the climate in which the distilled spirit is produced, the longer it is aged.Most distillates have greater than 40-45 % alcohol content. In order to be drinkable, they have to be watered down.The distilled spirits still contain a variety of flavor and aroma compounds from the original mash, the fermentation process, the Maillard reaction in the still, or from the wood barrels in the aging process. Some of these compounds can cause a cloudy or hazy appearance to the distilled spirits.Distillers will often cool the spirits to between 0 and -10 °C.After cold storage, the distilled spirits are filtered to remove any precipitates.The bottling of the distilled spirits is straightforward.There are many flavors in distilled spirits. It is highly dependent upon the original raw materials, yeast fermentation process, presence of any microbial contaminants, aging, etc.However, distillation can intensify flavors that are found in the middle-run, but many other flavors do not get transferred from the pot to the distillate.It is important to note that the addition of flavorings, sugars or other sweetening products after distillation is forbidden for distilled beverages such as rum, whisky, fruit distillates or wine brandy. The addition of caramel in fruit distillates is not allowed, while whiskey is allowed plain caramel coloring only.The most common spirits are those derived from grains (whiskey, vodkas), grapes (cognac, brandy), molasses (rum), and agave (tequila).Whisky is a distilled beverage from cereal grains and matured in barrels. There are different regional variations on this drink. The malt from corn, barley, rye, or wheat is mashed in a process similar to beer. The wort is then directly distilled.Brandy is a distilled wine beverage.Rum is a distilled beverage from sugar cane.Tequila is a distilled beverage from agave.An eau de vie is a clear fruit brandy that is produced by means of fermentation and double distillation. For example, Framboise is a double distilled raspberry brandy. Unlike liqueurs, eae de vie are not sweetened. Although eau de vie is a French term, similar beverages are produced in other countries (e.g. German Schnapps, German Kirschwasser, Turkish rakı, Hungarian pálinka, and Sri Lankan coconut arrack).Liqueurs are drinks made by adding fruit, herbs or nuts to neutral distilled spirits. Usually a distilled beverage like vodka is used as it is mostly alcohol and little flavoring. They are often also heavily sweetened. They are often served with dessert. You might drink it straight, with coffee, used in cocktails, or in cooking.Coldea, Mudura & Socaciu, Chapter 6: Advances in Distilled Beverages Authenticity and Quality Testing, In Ideas and Applications Toward Sample Preparation for Food and Beverage Analysis, M. Stauffer, Ed., IntechOpen, 2017.S. Canas, Phenolic Composition and Related Properties of Aged Wine Spirits: Influence of Barrel Characteristics. A Review, Beverages, 2017, 3, 55-77.Schaller, Structure and Reactivity, Purification of Molecular Compounds, PM3: DistillationN. Spaho, Ch 6: Distillation Techniques in the Fruit Spirits Production, In Distillation – Innovative Applications and Modeling, M. Mendes, Ed., IntechOpen, 2017.This page titled 1.16: Distilled Spirits is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Kate Graham.

ATP/ADP-Gutow Draft

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Metabolism/ATP_ADP-Gutow_Draft

Adenosine-5'-triphosphate (ATP) is comprised of an adenine ring, a ribose sugar, and three phosphate groups. ATP is often used for energy transfer in the cell. The enzyme ATP synthase produces ATP from ADP or AMP + Pi using energy produced from metabolism in the mitochondria. ATP has many uses. It is used as a coenzyme, in glycolysis, for example. ATP is also found in nucleic acids in the processes of DNA replication and transcription. In a neutral solution, ATP has negatively charged groups that allow it to chelate metals. Usually, Mg2+ stabilizes it.ATP is a molecule which can hydrolyze to ADP and inorganic phosphate when it is in water. The formation of solvated ADP and hydrogen phosphate from solvated ATP and water has a ΔG of -30.5 kJ/mol. The negative ∆G means that the reaction is spontaneous (given an infinite amount of time it will proceed) and produces a net release of energy. However, because it requires energy to rupture the P-O bond connecting the phosphate that leaves ATP, ATP molecules do not instantly fall apart and can be used to transport useful energy around the cell. The energy required to rupture the bond contributes to the activation barrier that prevents the reaction from happening instantly.At pH 7 the balanced reaction for hydrolysis is:\[ATP ^{4-} + H_2O \rightleftharpoons ADP^{3-} + HPO_4^{2-} + H^+\] ∆G = -30.5 kJATP is the primary energy transporter for most energy-requiring reactions that occur in the cell. The continual synthesis of ATP and the immediate usage of it results in ATP having a very fast turnover rate. This means that ADP is synthesized into ATP very quickly and vice versa. For example, it takes only a few seconds for half of the ATP molecules in a cell to be converted into ADP to be used in driving endergonic (non-spontaneous) reactions and then converted back into ATP using exergonic (spontaneous) reactions.ATP is useful in many cell processes such as glycolysis, photosynthesis, beta oxidation, anaerobic respiration, active transport across cell membranes (as in the electron transport chain), and synthesis of macromolecules such as DNA.ATP/ADP-Gutow Draft is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

ATP/ADP

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Metabolism/ATP_ADP

Adenosine-5'-triphosphate (ATP) is comprised of an adenine ring, a ribose sugar, and three phosphate groups. ATP is often used for energy transfer in the cell. ATP synthase produces ATP from ADP or AMP + Pi. ATP has many uses. It is used as a coenzyme, in glycolysis, for example. ATP is also found in nucleic acids in the processes of DNA replication and transcription. In a neutral solution, ATP has negatively charged groups that allow it to chelate metals. Usually, Mg2+ stabilizes it.ATP is an unstable molecule which hydrolyzes to ADP and inorganic phosphate when it is in equilibrium with water. The high energy of this molecule comes from the two high-energy phosphate bonds. The bonds between phosphate molecules are called phosphoanhydride bonds. They are energy-rich and contain a ΔG of -30.5 kJ/mol.Removing or adding one phosphate group interconverts ATP to ADP or ADP to AMP. Breaking one phosphoanhydride bond releases 7.3 kcal/mol of energy.\[\ce{ATP + H_2O \rightarrow ADP + P_{i}} \tag{ΔG = -30.5 kJ/mol}\]\[\ce{ATP + H_2O \rightarrow AMP + 2 P_{i} } \tag{ΔG = -61 kJ/mol}\]\[\ce{2 ADP + H_2O \rightarrow 2 AMP + 2 P_{i}} \tag{ΔG = -61 kJ/mol}\]At pH 7,\[\ce{ATP ^{4-} + H_2O \rightleftharpoons ADP^{3-} + HPO_4^{2-} + H^{+}} \nonumber\]ATP is the primary energy transporter for most energy-requiring reactions that occur in the cell. The continual synthesis of ATP and the immediate usage of it results in ATP having a very fast turnover rate. This means that ADP is synthesized into ATP very quickly and vice versa. For example, it takes only a few seconds for half of the ATP molecules in a cell to be converted into ADP to be used in driving endergonic (non-spontaneous) reactions and then converted back into ATP using exergonic (spontaneous) reactions.ATP is useful in many cell processes such as glycolysis, photosynthesis, beta oxidation, anaerobic respiration, active transport across cell membranes (as in the electron transport chain), and synthesis of macromolecules such as DNA.ATP/ADP is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Adrenergic Drugs

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Medicinal_Chemistry/Adrenergic_Drugs

The compounds ordinarily classified as central stimulants are drugs that increase behavioral activity, thought processes, and alertness or elevate the mood of an individual. These drugs differ widely in their molecular structures and in their mechanism of action. Thus, describing a drug as a stimulant does not adequately describe its medicinal chemistry. The convulsions induced by a stimulant such as strychnine, for example, are very different from the behavioral stimulation and psychomotor agitation induced by a stimulant such as amphetamine.The three main catacholamines (chatecol is ortho-dihydroxybenzene) are epinephrine EP, norepinephrine NE, and dopamine DA. A host of physiological and metabolic responses follows stimulation of sympathetic nerves in mammals is usually mediated by the neurotransmitter norepinephrine. As part of the response to stress, the adrenal medulla is also stimulated, resulting in elevation of the concentrations of EP and NE in the circulation. The actions of these two catecholamine are very similar at some sites but differ in significantly at others. For example, both compounds stimulate the myocardium; however, EP dilates blood vessels to skeletal muscle, whereas NE has a minimal constricting effect on them. DA is found predominantly in the basal ganglia of the CNS and is found in very low levels in peripheral tissues.The synthesis of the neurotransmitters DA and NE and EP and the hormones NE and EP takes place by a pathway that involves 5 enzymes (see figure below). Tyrosine is generally considered the starting point, although phenylalanine hydroxylase can hydroxylate phenylalanine to tyrosine in the event that there is a tyrosine deficiency. Tyrosine hydroxylase (structure) is the rate-limiting enzyme in this pathway. Its addition of the 3-OH yielding L-3, 4-dihydroxyphenylalanine (L-DOPA) requires O2, tetrahydropteridine, and Fe2+ as cofactors. One of the oxygen atoms in O2 is incorporated into an organic substrate and the other is reduced to water. Because this is the rate-limiting step, inhibition of this enzyme is the most likely way to reduce NE, DA, or EP levels significantly. Particularly are the a-methyltyrosine analogs, especially those containing an iodine atom in the benzene ring. The drug a -methyltyrosine is useful in the management of malignant hypertension and in pheochromocytoma. The latter is a chromaffin cell tumor that produces and spills copious amounts of NE and EP into the circulation.DOPA is then converted to dopamine by the enzyme DOPA decarboxylase. The cofactor for this enzyme is pyridoxal (the aldahyde form of pyridoxine, vitamin B6). The copper-containing enzyme dopamine-beta-monooxygenase then converts dopamine to NE and in the end norepinephrine N-methyltransferase converts NE to EP. Genetic defaults in, or complete absence of, the first of these 5 enzymes (Phenylalanine Hydroxylase) leads to a disease called phenylketoneuria PKU, which will lead to severe mental disorder if not treated at an early stage after birth.Research experiments using different drugs that mimic the action of norepinephrine on sympathetic effector organs have shown that there are two major types of adrenergic receptors, alpha receptors and beta receptors. The beta receptors in turn are divided into beta1 and beta 2 receptors because certain drugs affect only some beta receptors. Also, there is a less distinct division of alpha receptors into alpha1 and alpha 2 receptors.Just as in the muscarinic receptor, and most other G protein-coupled receptors that bind biogenic amines, the adrenergic receptors possess an aspartate residue in the third transmembrane domain. The aspartate residue appears to interact with the amine residue of norepinephrine and other adrenergic ligands. Conserved serine residues in TM5 may play a role in the binding of adrenergic ligands through hydrogen bond interactions. In addition, aromatic amino acid residues, such as a phenylalanine in TM6, may contribute to the binding of ligands through pi - pi interactions.Norepinephrine and epinephrine, both of which are secreted into the blood by the adrenal medulla, have somewhat different effects in exciting the alpha and beta receptors. Norepinephrine excites mainly alpha receptors but excites the beta receptors to a less extent as well. On the other hand, epinephrine excites both types of receptors approximately equally. Therefore, the relative effects of norepinephrine and epinephrine on different effector organs are determined by the types of receptors in the organs. If they are all beta receptors, epinephrine will be the more effective excitant. It should be emphasised that not all tissues have both of these receptors. Usually they are associated with only one type of receptor or the other.EP dilates blood vessels (relaxes smooth muscle) in skeletal muscle and liver vascular beds; NE constricts the same vascular beds. EP decreases resistance in the hepatic and skeletal vascular smooth muscle beds; NE increases resistance. In contrast to their opposite effects on vascular smooth muscle of the liver and skeletal muscle, both EP and NE cause vasoconstriction (contraction of smooth muscle) in blood vessels supplying the skin and mucosa. EP decreases diastolic blood pressure; NE increases diastolic blood pressure. EP relaxes bronchial smooth muscle; NE has little effect. Both EP and NE stimulate an increased rate of beating when applied directly to a heart muscle removed from the body and isolated from nervous input. In contrast, NE given intravenously causes a profound reflex bradycardia due to a baroreceptor/vagal response (and increased release of acetylcholine onto the heart) in response to the vasopressor effect of NE.The binding of the adrenergic receptor causes a series of reactions that eventually results in a characteristic response.Two of the proteins that are phosphorylated in this process breakdown glycogen and stop glycogen synthesis.There are three main ways in which catacolamines are removed from a receptor - recycling back into the presynaptic neuron by an active transport reuptake mechanism, degredation to inactive compounds through the sequential actions of catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO), and simple diffusion (see figure below).Schematic representation of an adrenergic junction. Copyright © 1996-1997 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.MAO catalyzes the oxidative deamination of catecholamines, serotonin, and other monoamines. It is one of several oxydase-type enzymes who's coenzyme is the flavin-adenine-dinucleatide (FAD) covalently bound as a prosthetic group. The isoallozazine ring system is viewed as the catalytically functional component of the enzyme. In this view N-5 and C-4a is where the redox reaction takes place. Although the whole region undoubtedly participates.Norepinephrine (NE) is the neurotransmitter of most postganglionic sympathetic fibers and many central neurons (eg, locus ceruleus, hypothalamus). Upon release, NE interacts with adrenergic receptors. This action is terminated largely by the re-uptake of NE back into the prejunctional neurons. Tyrosine hydroxylase and MAO regulate intraneuronal NE levels. Metabolism of NE occurs via MAO and catechol-O-methyltransferase to inactive metabolites (eg, normetanephrine, 3-methoxy-4-hydroxyphenylethylene glycol, 3-methoxy-4-hydroxymandelic acid).Epinephrine is a potent stimulator of both a and b -adrenergic receptors, and its effects on target organs are thus complex. Most of the effects which occur after injection are listed in the table on a and b -receptors shown above. Particularly prominent are the actions on the heart and the vascular and other smooth muscle. Epinephrine is one of the most potent vasopressor drugs known. Given intravenously it evokes a characteristic effect on blood pressure, which rises rapidly to a peak that is proportional to the dose. The increase is systolic pressure is greater than diastolic pressure, so that the pulse pressure increases. As the response wanes, the mean pressure falls below normal before returning to normal. The mechanism of the rise in blood pressure due to epinephrine is three fold; a direct myocardial stimulation that increases the strength of ventricular contraction; and increased heart rate; and most important, vasoconstriction in many vascular beds, especially the in the vessels of the skin, mucosa, and kidney, and constriction in the veins. Due to this increased blood pressure and to powerful b 2-receptor vasodilator action that is partially counterbalanced by vasoconstrictor action on the a receptors that are also present, blood flow to the skeletal muscles and central nervous system is increased.The effects of epinephrine on the smooth muscles of different organs and systems depend upon the type of adrenergic receptor in the muscle. It has powerful bronchiodilatior action, most evident when bronchial muscle is contracted as in bronchial asthma. In such situations, epinephrine has a striking therapeutic effect as a physiological antagonist to the constrictor influences since it is not limited to specific competitive antagonism such as occurs with antihistaminic drugs against histamine-induced bronchiospasm.Epinephrine has a wide variety of clinical uses in medicine and surgery. In general, these are based on the actions of the dug on blood vessels, heart, and bronchial muscle. The most common uses of epinephrine are to relieve respiratory distress due to bronchiospasm and to provide rapid relief of hypersensitivity reactions to drugs and other allergens. Its cardiac effects may be of use in restoring cardiac rhythm in patients with cardiac arrest. It is also used as a topical hemostatic on bleeding surfaces. NorepinephrineNorepinephrine is the chemical mediator liberated by mammalian postgangionic adrenergic nerves. It differs from epinephrine only by lacking the methyl substitution in the amino group. Norepinephrine constitutes 10 to 20% of the catecholamine content of human adrenal medulla. Norepinephrine is a potent agonist at a receptors and has little action on b 2 receptors; however, it is somewhat less potent than epinephrine on the a receptors of most organs. Most of the effects which occur after injection are listed in the table on a and b -receptors shown above Norepinephrine has only limited therapeutic value. Amphetamine and MethamphetamineAmphetamine, racemic b-phenylisopropylamine, has powerful CNS stimulant actions in addition to the peripheral a and b actions common to indirectly acting sympathomimetic drugs. Unlike epinephrine, it is effective after oral administration and its effects last for several hours. Although amphetamine and methamphetamine are almost structurally identical to norepinephrine and epinephrine, these drugs have an indirect sympathomimetic action rather than directly exciting adrenergic effector receptors. Their effect is to cause release of norepinephrine from its storage vesicles in the sympathetic nerve endings The release of norepinephrine in turn causes the sympathetic effects.Ephedrine occurs naturally in various plants. It was used in China for at least 2000 years before being introduced into Western medicine in 1924. Its central actions are less pronounced than those of the amphetamines. Ephedrine stimulates both a and b receptors and has clinical uses related to both these types of action. The drug owes part of its peripheral action to the release of norepinephrine, but it also has direct effects of receptors.Since ephedrine contains two chiral carbon atoms, four compounds are possible. Clinically, D-ephedrine is used to a large extent as an anti-asthmatic and, formerly, as a presser amine to restore low blood pressure as a result of trauma. L-pseudo-ephedrine is used primarily as a nasal decongestant.Ephedrine differs from epinephrine mainly in its efficacy after oral administration, its much longer duration of action, its more pronounced central actions, and its much lower potency. Cardiovascular effects of ephedrine are in many ways similar to those of epinephrine, but they persist about ten times as long. The drug elevates the systolic and diastolic pressure in man, and pulse pressure increases. Bronchial muscle relaxation is less prominent but more sustained with ephedrine than with epinephrine. The main clinical uses of ephedrine are in bronchiospasm, as a nasal decongestant, and certain allergic disorders, The drug is also used, although perhaps unwisely, as a weight loss agent.The monoamine oxidase inhibitors (MAOIs) comprise a chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. These drugs have numerous other effects, many of which are still poorly understood. For example, they lower blood pressure and were at one time used to treat hypertension. Their use in psychiatry has also become very limited as the tricyclic antidepressants have come to dominate the treatment of depression and allied conditions. Thus, MAOIs are used most often when tricyclic antidepressants give unsatisfactory results. In addition, whereas severe depression may not be the primary indication for these agents, certain neurotic illnesses with depressive features, and also with anxiety and phobias, may respond especially favorably.Two main problems are associated with the MAOIs. The first is that an amino acid called "tyramine" may cause a hypertensive reaction in some people taking MAOIs. Therefore, foods containing tyramine must be avoided. Alcohol and caffeine must also be eliminated from the diet. Certain medications may react dangerously when combined with MAOIs. Therefore, it is crucial to tell the prescribing doctor about medications (including over-the-counter) you are taking. The second problem associated with MAOIs is the possibility of side effects. MAOIs not only inhibit MAO but other enzymes as well, and they interfere with the hepatic metabolism of many drugs. The dietary restrictions and side effects deter many people from staying on MAOIs.Phenelzine is the hydrazine analog of phenylethylamine, a substrate of MAO. This and several other MAOIs, such as isocarboxazide, are structurally related to amphetamine and were synthesized in an attempt to enhance central stimulant properties. CocaineCocaine blocks the reuptake of dopamine by presynaptic neurons. More about this can be found under the topic Illegal Drugs. DopamineDopamine is the immediate metabolic precursor of NE and EP; it is a central neurotransmitter and possesses important intrinsic pharmacological properties. DA is a substrate for both MAO and COMT and thus is ineffective when administered orally. Parkinson's Disease. Parkinson's disease can be characterized as having a DA deficiency in the brain. The pathology can be traced to certain large neurons in the substantia nigra in the basal ganglia, whose degeneration is directly related to DA deficiency. One of the principle roles of the basal ganglia is to control complex patterns of motor activity. When there is damage to the basal ganglia one's writing becomes crude.Logic would dictate that increasing brain levels of DA should ameliorate symptoms of Parkinson's disease. Direct parental DA administration is useless since the compound does not penetrate the Blood-brain barrier. It is shown that oral dosing with L-DOPA can successfully act as a pro-drug to the extent it enters the brain and is then decarboxylated to DA there. The clinical results in terms of decreased tremors and rigidity are dramatic. However, there are complications which produce intense side effects including nausea and vomiting, that are presumably due to chemoreceptor trigger zone stimulation by large amounts of DA produced peripherally. The reason for this situation is the relatively high peripheral levels of decarboxylase enzyme compared with brain concentrations. Thus 95% of a given oral dose was converted to DA before reaching the brain to be decarboxylated there. This can be prevented using L-DOPA in combination with a drug called carbidopa (more).Amantadine, introduced as an antiviral agent for the influenza was unexpectedly found to cause symptomatic improvement of patients with parkinsonism. Amantadine is a basic amine like dopamine, but the lipophilic nature of the cage structure enhances its ability to cross the blood brain barrier. This drug acts by releasing dopamine from intact dopaminergic terminals that remain in the nigrostraeatum of patients with Parkinson's disease. Because of this facilitated release of dopamine it appears that the therapeutic efficacy of amantadine is enhanced by the concurrent administration of levodopa. Amantadine has also been shown to delay the re-uptake of dopamine by neural cells, and it may have anticholinergic effects as well. A three dimensional view of amantadine may provide a better understanding of the structure.The above therapies are based on the manipulation of endogenous stores of dopamine. Dopamine agonists can stimulate the receptor directly and are of therapeutic value. Some of the drugs acting as dopaminergic agonists include the ergot alkaloid derivative bromocriptine. Bromocriptine is used particularly when L-DOPA therapy fails during the advanced stages of the disease. Bromocriptine is a derivative of lysergic acid (a precursor for LSD). Its structure is shown below. The addition of the bromine atom renders this alkaloid a potent dopamine agonist and virtually all of its actions result from stimulation of dopamine receptors.Schizophrenia. Schizophrenia results from excessive excitement of a group of neurons that secrete dopamine in the behavioral centers of the brain, including in the frontal lobes. Therefore drugs used to treat this disorder decrease the level of dopamine excreted from these neurons or antagonize dopamine. We will discuss these drugs in detail later under the topic Psychoactive Drugs.Strychnine does not directly affect adrenergic mechanisms, and technically should not be listed in this category. However, its stimulating affects are a result of adrenergic mechanisms. In addition, strychnine has no demonstrated therapeutic value, despite a long history of unwarranted popularity. However, the mechanism of action of strychnine is thoroughly understood, and it is a valuable pharmacological tool for studies of inhibition in the CNS. Poisoning with strychnine results in a predictable sequence of dramatic symptoms that may be lethal unless interrupted by established therapeutic measures.Strychnine is the principle alkaloid present in nux vomica, the seeds of a tree native to India, Stychnos nux-vomica. The structural formula for strychnine is:Strychnine produces excitation of all portions of the CNS. This effect, however, does not result from direct synaptic excitation. Strychnine increases the level of neuronal excitability by selectively blocking inhibition. Nerve impulses are normally confined to appropriate pathways by inhibitory influences. When inhibition is blocked by strychnine, ongoing neuronal activity is enhanced and sensory stimuli produce exaggerated reflex effects.Strychnine is a powerful convulsant, and the convulsion has a characteristic motor pattern. Inasmuch as strychnine reduces inhibition, including the reciprocal inhibition existing between antagonistic muscles, the pattern of convulsion is determined by the most powerful muscles acting at a given joint. In most laboratory animals, this convulsion is characterized by tonic extension of the body and of all limbs. The convulsant action of strychnine is due to interference with post synaptic inhibition that is mediated by glycine. Glycine is an important inhibitory transmitter to motorneurons and interneurons in the spinal cord, and strychnine acts as a selective, competitive antagonist to block the inhibitory effects of glycine at all glycine receptors. Competitive receptor-binding studies indicate that both strychnine and glycine interact with the same receptor complex, although possibly at different sites.The first symptoms of strychnine poisoning that is noticed is stiffness of the face and neck muscles. Heightened reflex excitability soon becomes evident. Any sensory stimulus may produce a violent motor response. In the early stages this is a coordinated extensor thrust, and in the later stages it may be a full tetanic convulsion. All voluntary muscles, including those of the face, are soon in full contraction. Respiration ceases due to the contraction of the diaphragm and the thoracic and abdominal muscles.Edward B. Walker (Weber State University)Adrenergic Drugs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Amino Acids

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Amino acids are exactly what they say they are! They are compounds containing an amino group, -NH2, and a carboxylic acid group, -COOH. The biologically important amino acids have the amino group attached to the carbon atom next door to the -COOH group. They are known as 2-amino acids and are also known as alpha-amino acids. Thumbnail: 3D model of L-tryptophan. (Public Domain; Benjah-bmm27).Amino Acids is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Analgesics and Anti-Inflammatory Agents

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The anti-inflammatory, analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and side effects. The prototype is aspirin; hence these compounds are often referred to as aspirin-like drugs. All aspirin-like drugs are antipyretic, analgesic, and anti-inflammatory, but there are important differences in their activities. For example, acetaminophen is antipyretic and analgesic but is only weakly anti-inflammatory. The reason for the differences are not clear; variations in the sensitivity of enzymes in the target tissues may be important.When employed as analgesics, these drugs are usually effective only against pain of low-to-moderate intensity, particularly that associated with inflammation. Aspirin drugs do not change the perception of sensory modalities other than pain. The type of pain is important; chronic postoperative pain or pain arising from inflammation is particularly well controlled by aspirin-like drugs, whereas pain arising from the hollow viscera is usually not relieved.As antipyretics, aspirin-like drugs reduce the body temperature in feverish states. Although all such drugs are antipyretics and analgesics, some are not suitable for either routine or prolonged use because of toxicity; phenylbutaxone is an example. This class of drugs finds its chief clinical application as anti inflammatory agents in the treatment of musculoskelatal disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In general, aspirin-like drugs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury.There has been substantial progress in elucidating the mechanism of action of aspirin-like drugs, and it is now possible to understand why such heterogeneous agents have the same basic therapeutic activities and often the same side effects. Indeed, their therapeutic activity appears to depend to a large extent upon the inhibition of a defined biochemical pathways responsible for the biosynthesis of prostaglandins (see figure below) and related autacoids.Aspirin-like drugs inhibit the conversion of arachidonic acid to the unstable endoperoxide intermediate, PGG2, which is catalyzed by the cyclooxygenase. Individual agents have differing modes of inhibitory activity on the cyclooxygenase. Aspirin itself acetylates a serine at the active site of the enzyme. Platelets are especially susceptible to this action because (unlike most other cells) they are incapable of regenerating the enzyme, presumably because they have little or no capacity for protein biosynthesis. In practical terms this means that a single dose of aspirin will inhibit the platelet cyclooxygenase for the life of the platelet (8 to 10 days); in man a dose as small as 40 mg per day is sufficient to produce this effect. In contrast to aspirin, salicylic acid has no acetylating capacity and is almost inactive against cyclooxygenase in vitro. Nevertheless, it is as active as aspirin in reducing the synthesis of prostaglandins in vivo. The basis of this action and, thus, of the anti-inflammatory effect of salicylic acid is not clearly understood. Since aspirin is rapidly hydrolyzed to salicylic acid in vivo (half-life in human plasma, approximately 15 minutes), the acetylated and nonacetylated species probably act as pharmacologically distinct entities.Most of the other common aspirin-like drugs are irreversible inhibitors of the cyclooxygenase, although there are some exceptions. For indomethacin, the mode of inhibition is particularly complex and probably involves a site on the enzyme different from that which is acetylated by aspirin.Prostaglandins are associated particularly with the development of pain that accompanies injury or inflammation. Large doses of PGE2 or PGF2a , given to women by injection to induce abortion, cause intense local pain. Prostaglandins can also cause headache and vascular pain when infused intravenously in man. While the doses of prostaglandins required to elicit pain are high in comparison with the concentrations expected in vivo, induction of hyperalgesia occurs when minute amounts of PGE1 are given intradermally to man. Furthermore, in experiments in man where separate infusions of PGE1, bradykinin, or histamine caused no pain, marked pain was experienced when PGE1 was added to bradykinin or histamine. When PGE1 was infused with histamine, itching was also noted.The hypothalamus regulates the set point at which body temperature is maintained. In fever, this set point is elevated, and aspirin-like drugs promote its return to normal. These drugs do not influence body temperature when it is elevated by such factors as exercise or increases in the surrounding temperature.Fever may be a result of infection, tissue damage, inflammation, graft rejection, malignancy, or other disease states. A multitude of microorganisms can cause fever. There is evidence that bacterial endotoxins act by stimulating the biosynthesis and release by neutrophils and other cells of an endogenous pyrogen, a protein with a molecular weight of 10,000 to 20,000. The current view is that the endogenous pyrogen passes from the general circulation into the central nervous system, where it acts upon discrete sites within the brain, especially the preoptic hypothalamic area. There is evidence that the resultant elevation of body temperature is mediated by the release of prostaglandins and that aspirin-like drugs suppress the effects of endogenous pyrogen by inhibiting the synthesis of these substances. The evidence includes the ability of prostaglandins, especially PGE2, to produce fever when infused into the cerebral ventricles or when infected into the hypothalamus. Fever is a frequent side effect of prostaglandins when they are administered to a women as abortifacients. Moreover some studies have demonstrated an increase in prostaglandin-like substances in the cerebrospinal fluid when endogenous pyrogen is injected intravenously. The fever produced by the administration of pyrogen, but not that by prostaglandins, is reduced by aspirin-like drugs.Aspirin is very useful, but it has many side effects and therefore must be used carefully. Like most powerful drugs, an overdose of aspirin or salicylates can be fatal. If a child or adult takes an overdose of aspirin, induce vomiting to empty the unabsorbed medication from the stomach (if the person is still awake and conscious). Obtain emergency medical care right away. The most common side effects of aspirin are heartburn and other symptoms of stomach irritation such as indigestion, pain, nausea, and vomiting. The stomach irritation may lead to bleeding from the stomach, which may cause black stools. These symptoms may be reduced by taking aspirin with meals, with an antacid, with a glass of milk, or by taking enteric-coated or timed-release aspirin. Also, it is best not to take aspirin with alcohol or coffee (or other beverages containing caffeine, such as tea or cocoa and many soft drinks). Alcohol and caffeine make the stomach more sensitive to irritation. The non aspirin salicylate preparations sometimes are less irritating to the stomach and may be substituted for aspirin by your doctor. A few people develop asthma, hay fever, nasal congestion, or hives from aspirin or non-steroid anti-inflammatory drugs (NSAIDs). These people should never take aspirin, nor should people who have active stomach or duodenal ulcers. Anyone who has ever had a peptic ulcer should be very careful about taking aspirin because it can lead to a recurrence. Aspirin is known to interfere with the action of the platelets. As a result, some people who take a lot of aspirin experience easy bruising of the skin. Therefore, people who have major bleeding problems should not take aspirin. Also, keep in mind that aspirin should not be taken for 10-14 days before surgery (including surgery in the mouth) to avoid excessive bleeding during or after the operation. These side effects probably depend on aspirin-like drugs' ability to block endogenous prostaglandin biosynthesis. Platelet function appears to be disturbed because aspirin-like drugs prevent the formation by the platelets of thrombozane A2 (TXA2), a potent aggregating agent. This accounts for the tendency of these drugs to increase the bleeding time.Aspirin increases oxygen consumption by the body, increasing carbon dioxide production-an effect that stimulates respiration. Therefore, overdose with aspirin is often characterized by marked increases in respiratory rate, which cause the overdosed individual to appear to pant. This occurrence results in other, severe, metabolic consequences.Prolongation of gestation by aspirin-like drugs has been demonstrated in both experimental animals and the human female. Furthermore, prostaglandins of the E and F series are potent uterotropic agents , and their biosynthesis by the uterus increases dramatically in the hours before parturition. It is thus hypothesized that prostaglandins play a major role in the initiation and progression of labor and delivery. High doses of salicylate may cause ringing in the ears and slight deafness. Sometimes, however, these symptoms indicate mild overdose, which could become more serious. Aspirin and NSAIDs sometimes affect the normal function of the kidneys and aspirin-like drugs promote the retention of salt and water by reducing the prostaglandin-induced inhibition of both the reabsorption of chloride and the action of antidiuretic hormone. This may cause edema in some patients with arthritis who are treated with an aspirin-like drug. Recent reports have said there could be a link between the use of aspirin and the development of Reye's syndrome. Reye's syndrome is a rare but possibly fatal disease seen most often in children and teenagers. It usually affects those recovering from chicken pox or a viral illness such as the flu. These reports have raised concern in pediatricians (doctors who specialize in treating children) and parents of children with arthritis who need to take large doses of aspirin to control their disease. AspirinIn the U.S., about 10 to 20 thousand tons of aspirin are consumed each year; it is our most popular analgesic. Aspirin is one of the most effective analgesic, antipyretic, and anti-inflammatory agents.Chemical structureAcetaminophen is an effective alternative to aspirin as an analgesic and antipyretic agent. However, its anti-inflammatory effect is minor and not clinically useful. It is commonly felt that acetaminophen may have fewer side effects than aspirin, but it should be noted that an acute overdose may produce severe or even fatal liver damage. Acetaminophen does not inhibit platelet aggregation and therefore is not useful for preventing vascular clotting.Side effects are usually fewer than those of aspirin; the drug produces less gastric distress and less ringing in the ears. However, as stated previously, overdose can lead to severe damage of the liver.Acetaminophen has been proved to be a reasonable substitute for aspirin when analgesic or antipyretic effectiveness is desired, especially in patients who cannot tolerate aspirin. This might include patients with peptic ulcer disease of gastric distress or those in whom the anticoagulant action of aspirin might be undesirable. Aspirin is often combined with acetaminophen in a single tablet for relief of arthritis and other painful conditions. Sometimes other drugs such as caffeine, an antihistamine, nasal drying agents, and sedatives are also added. Although some of these preparations may have special uses for certain acute conditions such as a cold or a headache, they should not be taken for a chronic (long-term) form of arthritis. If a combination is required, each drug should be prescribed separately. The dose of each should be adjusted individually to achieve the greatest benefit with the fewest side effects.Researchers attribute the pain-relieving activity of acetaminophen to the drug's ability to elevate the pain threshold, although the precise mechanisms involved in this process have not been clearly identified. The antipyretic, or fever-reducing, effect of acetaminophen is far better understood. Research shows that the drug inhibits the action of fever-producing agents on the heat-regulating centers of the brain by blocking the formation and release of prostaglandins in the central nervous system. However, unlike aspirin and other NSAIDs, acetaminophen has no significant effect on the prostaglandins involved in other body processes.Despite claims to the contrary, stomach upset and hepatic toxicity are statistically as much a problem with acetaminophen as with aspirin-like drugs. Acetaminophen is normally metabolized in the liver and kidney by P450 enzymes. No toxicity is observed with therapeutic doses, however, after ingestion of large quantities (>2,000 mg/kg), a highly reactive metabolite, N-acetyl-p-benzoquinoneimine, is generated (see figure below). This species is electrophilic intermediate which is conjugated with glutathion to a non-toxic compound. Overdosing depletes glutithione and N-acetyl-p-benzoquinone reacts with nucleophilic portions (sulfhdryl groups) of critical liver cell protein. This results in cellular dysfunction and hepatic and renal toxicity. Antidote treatment consists of amino acid supplements to replenish glutathione. The P450 metabolizing enzymes differ somewhat in character between the liver and kidney. Factors that enhance renal toxicity include chronic liver disease, possibly gender, concurrent renal insults, and conditions that alter the activity of P450-metabolizing enzyme systems.Other aspirin-like drugs include diflunisal, phenylbutazone, apazone, indomethacine, sulindac, fenamates, tolmetin, ibuprofen (see figure below), and piroxicam.Gold is not of course an aspirin-like drug. However, its end effect is similar to aspirin, so it will be briefly considered here. Gold in elemental form has been employed for centuries as an antipruritic (anti itch medication) to relieve the itching palm. At present, gold treatment includes different forms of gold salts used to treat rheumatoid arthritis and related diseases. In some people, it helps relieve joint pain and stiffness, reduce swelling and bone damage, and reduce the chance of joint deformity and disability.The significant preparations of gold are all compounds in which the gold is attached to sulfur. The three prominent drugs are aurothioglucose, auranofin, and gold sodium thiomalate.It takes months for gold compounds to leave the body. This means that side effects to gold therapy may take some time to resolve. Sometimes side effects even appear after the last gold injection. Rash and a metallic taste in the mouth are side effects of gold injections that may not seem serious at first. However, they are early warning signs for more serious reactions. If either of these side effects develop, the health care provider should be contacted promptly. Some side effects may cause multiple symptoms, not all of which may occur. Side effects with multiple symptoms are: The term opiate refers to any natural or synthetic drug that exerts actions upon the body similar to those induced by morphine, the major pain-relieving agent obtained from the opium poppy (Papaver somniferum). They were so highly regarded in the nineteenth century as remedies for pain, anxiety, cough, and diarrhea that some physicians referred to them as G.O.M.- `God's Own Medicine'. Opiates interact with what appear to be several closely related receptors, and they share some of the properties of certain naturally occurring peptides, the enkephalins, endorphins, and dynorphins.The term opium refers to the crude resinous extract obtained from the opium poppy. Crude opium contains a wide variety of ingredients, including morphine and codeine, both of which are widely used in medicine. The bulk of the ingredients of opium, however, consists of such organic substances as resins, oils, sugars, and proteins that account for more than 75 % of the weight of the opium but exert little pharmacological activity. Morphine is the major pain relieving drug found in opium, being approximately 10% of the crude exudate. Codeine is structurally close to morphine (see figs below), although it is much less potent and amounts to only 0.5% of the opium extract. Heroin does not occur naturally but is a semisynthetic derivative produced by a chemical modification of morphine that increases the potency (see figs. below). It takes only 3 mg. of heroin to produce the same analgesic effect as 10 mg of morphine. However, at these equally effective doses, it may be difficult to distinguish between the effects of the two compounds. In the CNS, there is reasonably firm evidence for four major categories of receptors, designated m, k, d , and s . To add confusion, there may well be subtypes of each of these receptors. Although there is considerable variation in binding characteristics and anatomical distribution among different species, inferences have been drawn from data that attempt to relate pharmacological effects to interactions with a particular constellation of receptors. For example, analgesia has been associated with both m and k receptors, while dysphoria or psychotomimetic (alteration of behavior or personality) effects have been ascribed to s receptors; based primarily on their localization in limbic regions of the brain, d receptors are thought to be involved in alterations of affective behavior. The actions of opioid drugs that are currently available have usually been interpreted with respect to the participation of only three types of receptors - m, k, and s ; at each, a given agent may act as an agonist, a partial agonist, or an antagonist (see table ). The m receptor is thought to meduate supraspinal analgesia, respiratory depression, euphoria, and physical dependance; the k receptor, spinal analgesia, miosis, and sedation; the s receptor, dysphoria, hallucinations, and respiratory and vasomotor stimulation.It has been observed that opioids can selectively inhibit certain excitatory inputs to identified neurons. For example, the iontophoretic administration (the induction of an ionized substance through intact skin by the application of a direct current) of morphine into the substantia gelatinosa suppresses the discharge of spinal neurons in lamina IV of the dorsal horn that is evoked by noxious stimuli (e.g. heat) without changing responses to other inputs. While a postsynaptic action at discrete dedritic sites cannot be excluded, these findings suggest that opioids selectively inhibit the release of excitatory transmitters from terminals of nerves carrying pain related stimuli. In other situations, postsynaptic actions of opioids appear to be important. For example, application of opioids to neurons in the locus ceruleus reduces both spontaneous discharge and responses evoked by noxious stimuli. However, excitation of the neurons by antidromic stimulation (i.e. causing the neurons to fire backwards) is also suppressed, and the cells are hyperpolarized by the drugs.Opioids have been observed to inhibit prostaglandin-induced increases in the accumulation of cyclic AMP in in brain tissue. Of potential relevance to mechanisms that underlie the phenomena of tolerance and withdrawal, the responses to prostaglandins recover in the continued presence of opioids.Opioid-induced analgesia is due to actions of several sites within the CNS and involves several systems of neurotransmitters. Although opioids do not alter the threshold or responsivity of afferent nerve endings to noxious stimulation or impair the conduction of the nerve impulses along peripheral nerves, they may decrease conduction of impulses of primary afferent fibers when they enter the spinal cord and decrease activity in other sensory endings. There are opioid binding sites (m receptors) on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. Morphine-like drugs acting at this site are thought to decrease the release of neurotransmitters, such as substance P, that mediate transmission of pain impulses.High doses of opioids can produce muscular rigidity in man, and both opioids and endogenous peptides cause catalepsy, circling, and stereotypical behavior in rats and other animals. These effects are probably related to actions at opioid receptors in the substania nigra and striatum, and involve interactions with both dopaminergic and GABA-ergic neurons.The mechanism by which opioids produce euphoria, tranquility, and other alterations of mood remains unsettled. Microinjections of opioids into the ventral tegmentum activate dopaminergic neurons that project to the nucleus accumbens. Animals will work to receive such injections, and activation (or disinhibition) of these neurons has been postulated to be a critical element in the reinforcing effects of opioids and opioid-induced euphoria. However, the administration of dopaminergic antagonists does not consistently prevent these reinforcing effects. The neural systems that mediate opioid reinforcement in the ventral tegmentum appear to be distinct from those involved in the classical manifestations of physical dependence and analgesia.Basic Effects of MorphineCNS. Morphine exerts a narcotic action manifested by analgesia, drowsiness, changes in mood, and mental clouding. The major medical action of morphine sought in the CNS is analgesia, which may usually be induced by doses below those that cause other effects on the CNS, such as sedation or respiratory depression. The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities (touch, vibration, vision, hearing, etc.) are not inhibited. Patients frequently report that the pain is still present but that they feel more comfortable. Continuous dull pain is relieved more effectively than sharp intermittent pain, but with sufficient amounts of morphine it is possible to relieve even the severe pain associated with renal or biliary colic. In fact, its analgesic action appears to result not from a decrease of pain impulses into the CNS but from an altered perception of the painful stimuli.Respiration. A second major action of morphine-like drugs is to depress respiration through interaction with m receptors located in the brainstem. At high doses, respiration may become so slow and irregular that life is threatened. In man, death from morphine poisoning is nearly always due to respiratory arrest. The primary mechanism of respiratory depression by morphine involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension (PCO2). High concentrations of opioid receptors, as well, as endogenous peptides, are found in the medullary areas believed to be important in ventilatory control. Respiratory depression is mediated by a subpopulation of m receptors (m 1), distinct from those that are involved in the production of analgesia (m 2). Thus, a 'pure' m 1-opioid agonist could theoretically produce analgesia with little respiratory depression.Cough. Opiates suppress the "cough center" which is also located in the brainstem, the medulla. Such an action is thought to underlie the use of opiate narcotics as cough suppressants. Codeine appears to be particularly effective in this action and is widely used for this purpose.Gastrointestinal Tract. The opiates have been used for centuries for the relief of diarrhea and for the treatment of dysentery, and these uses were developed long before these agents were used as analgesics or euphoiants. Opiates appear to exert their effect on the gastrointestinal tract primarily in the intestine, where peristaltic movements, which normally propel food down the intestine, are markedly diminished. Also, the tone of the intestine is greatly increased to the point where almost complete spastic paralysis of movement occurs. This combination of decreased propulsion and increased tone leads to a marked decrease in the movement of food through the intestine. This stasis is followed by a dehydration of the feces, which hardens the stool and further retards the advance of material. All these effects contribute to the constipating properties of opiates. Indeed, nothing more effective has yet been developed for treating sever diarrhea. Opiate AntagonistsNaloxone, when administered to normal individuals, produces no analgesia, euphoria, or respiratory depression. However, it rapidly precipitates withdrawal in narcotic-dependent individuals. Naloxone antagonizes the actions of morphine at all its receptors; however its affinity for m receptors is generally more than ten fold higher than for k or d receptors.The uses of naloxone include the reversal of the respiratory depression that follows acute narcotic intoxication and the reversal of narcotic-induced respiratory depression in newborns of mothers who have received narcotics. The use of naloxone is limited by a short duration of action and the necessity of parenteral route of administration.Naltrexone became clinically available in 1985 as a new narcotic antagonist. Its actions resemble those of naloxone, but naltrexone is well is well absorbed orally and is long acting, necessitating only a dose of 50 to 100 mg. Therefore, it is useful in narcotic treatment programs where it is desired to maintain an individual on chronic therapy with a narcotic antagonist. In individuals taking naltrexone, subsequent injection of an opiate will produce little or no effect. naltrexone appears to be particularly effective for the treatment of narcotic dependence in addicts who have more to gain by being drug-free rather than drug dependant.Edward B. Walker (Weber State University)Analgesics and Anti-Inflammatory Agents is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Anti-Cancer Drugs I

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Pharmaceuticals/Anti-Cancer_Drugs_I

The available anticancer drugs have distinct mechanisms of action which may vary in their effects on different types of normal and cancer cells. A single "cure" for cancer has proved elusive since there is not a single type of cancer but as many as 100 different types of cancer. In addition, there are very few demonstrable biochemical differences between cancerous cells and normal cells. For this reason the effectiveness of many anticancer drugs is limited by their toxicity to normal rapidly growing cells in the intestinal and bone marrow areas. A final problem is that cancerous cells which are initially suppressed by a specific drug may develop a resistance to that drug. For this reason cancer chemotherapy may consist of using several drugs in combination for varying lengths of time.Chemotherapy drugs, are sometimes feared because of a patient's concern about toxic effects. Their role is to slow and hopefully halt the growth and spread of a cancer. There are three goals associated with the use of the most commonly-used anticancer agents.Unfortunately, the majority of drugs currently on the market are not specific, which leads to the many common side effects associated with cancer chemotherapy. Because the common approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cells, the side effects are seen in bodily systems that naturally have a rapid turnover of cells iincluding skin, hair, gastrointestinal, and bone marrow. These healthy, normal cells, also end up damaged by the chemotherapy program.In general, chemotherapy agents can be divided into three main categories based on their mechanism of action.These agents work in a number of different ways. DNA building blocks are folic acid, heterocyclic bases, and nucleotides, which are made naturally within cells. All of these agents work to block some step in the formation of nucleotides or deoxyribonucleotides (necessary for making DNA). When these steps are blocked, the nucleotides, which arethe building blocks of DNA and RNA, can not be synthesized. Thus the cells can not replicate because they can nnot make DNA without the nucleotides. Examples of drugs in this class include 1) methotrexate (Abitrexate®),2) fluorouracil (Adrucil®), 3) hydroxyurea (Hydrea®), and 4) mercaptopurine (Purinethol®).These agents chemically damage DNA and RNA. They disrupt replication of the DNA and either totally halt replication or cause the manufacture of nonsense DNA or RNA (i.e. the new DNA or RNA does not code for anything useful). Examples of drugs in this class include cisplatin (Platinol®) and 7) antibiotics - daunorubicin (Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®).Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when a cell starts to divide itself into two new cells. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division. Examples of drugs in this class of 8) miotic disrupters include: Vinblastine (Velban®), Vincristine (Oncovin®) and Pacitaxel (Taxol®).In the 1950's a biochemical difference in metabolism related to the amino acid asparagine was found. Normal cells apparently can synthesize asparagine while leukemia cells cannot. If leukemia cells are deprived of asparagine, they will eventually die. In an almost unrecognized and parallel discovery, it was found that blood serum from guinea pigs and other South American rodents had antileukemia properties. The enzyme L-asparaginase was eventually identified as the anticancer agent. L-asparaginase was isolated and tested successfully on human leukemias. Eventually the enzyme asparaginase was also found and isolated from the bacteria, E. coli.If the enzyme L-asparaginase is given to humans, various types of leukemias can be controlled. Tumor cells, more specifically lymphatic tumor cells, require huge amounts of asparagines to keep up with their rapid, malignant growth. This means they use both asparagine from the diet as well as what they can make themselves (which is limited) to satisfy their large asparagines demand. L-asparaginase is an enzyme that destroys asparagine external to the cell. Normal cells are able to make all the asparagine they need internally whereas tumor cells become depleted rapidly and die.The enzyme converts asparagine in the blood into aspartic acid by a deamination reaction. The leukemia cells are thus deprived of their supply of asparagine and will die.Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid.Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it thinking that it is folic acid. In fact, methotrexate looks so good to the enzyme that it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Again, without DNA, no cell division.5-Fluorouracil (5-FU; Adrucil®, Fluorouracil, Efudex®, Fluoroplex®) is an effective pyrimidine antimetabolite. Fluorouracil is synthesized into the nucleotide, 5-fluoro-2-deoxyuridine. This product acts as an antimetabolite by inhibiting the synthesis of 2-deoxythymidine because the carbon - fluorine bond is extremely stable and prevents the addition of a methyl group in the 5-position. The failure to synthesize the thymidine nucleotide results in little or no production of DNA. Two other similar drugs include: gemcitabine (Gemzar®) and arabinosylcytosine (araC). They all work through similar mechanisms.Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual ChembookAnti-Cancer Drugs I is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Anti-Cancer Drugs II

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Pharmaceuticals/Anti-Cancer_Drugs_II

Hydroxyurea blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because hydroxyurea blocks the incorporation of the thymidine nucleotide into the DNA strand.Mercaptopurine, a chemical analog of the purine adenine, inhibits the biosynthesis of adenine nucleotides by acting as an antimetabolite. In the body, 6-MP is converted to the corresponding ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion of a compound called inosinic acid to adenine Without adenine, DNA cannot be synthesized. 6-MP also works by being incorporated into nucleic acids as thioguanosine, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis. Thioguanine is an antimetabolite in the synthesis of guanine nucleotides.Alkylating agents involve reactions with guanine in DNA. These drugs add methyl or other alkyl groups onto molecules where they do not belong. This in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA.There are six groups of alkylating agents: nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas. Cyclosporamide is a classical example of the role of the host metabolism in the activation of an alkylating agent and is one or the most widely used agents of this class. It was hoped that the cancer cells might posses enzymes capable of accomplishing the cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. Compare the top and bottom structures in the graphic on the left.A number of antibiotics such as anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, bind to DNA and inactivate it. Thus the synthesis of RNA is prevented. General properties of these drugs include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity.The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. These agents have a number of important effects including: intercalating (squeezing between the base pairs) with DNA affecting many functions of the DNA including DNA and RNA synthesis. Breakage of the DNA strand can also occur by inhibition of the enzyme topoisomerase II. At low concentrations dactinomycin inhibits DNA directed RNA synthesis and at higher concentrations DNA synthesis is also inhibited. All types of RNA are affected, but ribosomal RNA is more sensitive. Dactinomycin binds to double stranded DNA , permitting RNA chain initiation but blocking chain elongation. Binding to the DNA depends on the presence of guanine.Plant alkaloids like vincristine prevent cell division, or mitosis. There are several phases of mitosis, one of which is the metaphase. During metaphase, the cell pulls duplicated DNA chromosomes to either side of the parent cell in structures called "spindles". These spindles ensure that each new cell gets a full set of DNA. Spindles are microtubular fibers formed with the help of the protein "tubulin". Vincristine binds to tubulin, thus preventing the formation of spindles and cell division.Paclitaxel (taxol) was first isolated from the from the bark of the Pacific Yew (Taxus brevifolia). Docetaxel is a more potent analog that is produced semisynthetically. In contrast to other microtubule antagonists, taxol disrupts the equilibrium between free tubulin and mircrotubules by shifting it in the direction of assembly, rather than disassembly. As a result, taxol treatment causes both the stabilization of microtubules and the formation of abnormal bundles of microtubules. The net effect is still the disruption of mitosis.Intercalating agents wedge between bases along the DNA. The intercalated drug molecules affect the structure of the DNA, preventing polymerase and other DNA binding proteins from functioning properly. The result is prevention of DNA synthesis, inhibition of transcription and induction of mutations. Examples include: Carboplatin and Cisplatin.These related drugs covalently bind to DNA with preferential binding to the N-7 position of guanine and adenine. They are able to bind to two different sites on DNA producing cross-links, either intrastrand (within the same DNA molecule which results in inhibition of DNA synthesis and transcription.Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual ChembookAnti-Cancer Drugs II is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Anticancer Drugs

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Medicinal_Chemistry/Anticancer_Drugs

When fighting cancer, the entire population of neoplastic cells must be eradicated in order to obtain desired results. The concept of "total cell-kill" applies to chemotherapy as it does to other means of treatment: total excision of the tumor is necessary for surgical care, and complete destruction of all cancer cells is required for a cure with radiation therapy. By investigation of a model tumor system, the L1210 leukemia of mice, a number of important principles have been established as follows: The logical outgrowth of these concepts has been the attempt to achieve total cell-kill by the use of several chemotherapeutic agents concurrently or in rational sequences. The resulting prolonged survival of patients with acute lymphocytic leukemia through the use of such multiple-drug regimens has encouraged the application of these principles the treatment of other neoplasms.Fundamental advances continue in the chemotherapy of neoplastic diseases. The greatest progress in recent years has not been the discovery of new, useful chemotherapeutic agents but at the conceptual level: the design of more effective regimens for concurrent administration of drugs; the acquisition of knowledge of the mechanisms of action of many antitumor agents, which facilitates the design of new methods to prevent or minimize drug toxicity; the increased use of adjuvant chemotherapy (e,g., the design of chemotherapeutic approaches to destroy micrometastases and prevent the development of secondary neoplasms after removal of destruction of the primary tumor by surgery of irradiation); and increased knowledge about such vital processes as tumor initiation and the dissemination, implantation, and growth of metastases. Of great importance is recognition of the problems imposed by the heterogeneity of tumors, with the realization that individual tumors may contain many subpopulations of neoplastic cells that differ in crucial characteristics, such as karyotype, morphology, immunogenicity, rate of growth, the capacity to metastasize, and , significantly, responsiveness to antineoplastic agents. Information also continues to accumulate in the fields of molecular and cellular biology, resulting in a greater understanding of cellular division and differentiation, tumor immunology, and viral and chemical carcinogenisis. It is hoped that these discoveries will provide new targets for therapy.The chemotherapeutic alylating agents have in common the property of undergoing strongly electrophilic chemical reactions through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages (alkylation) with various nucleophilic substances, including such biologically important moieties as phosphate, amino, sulfydryl, hydroxyl, carbonyl, and imidozole groups. The cytotoxic and other effects of the alkylating agents are directly related to the alkylation of components of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with both monofunctional and bifunctional alkylators and may well represent the key target that determines the biological effects of these agents. It must be appreciated, however, that other atoms in the purine and pyrimidine bases of DNA-for example, the 1 or 3 nitrogens of adenine, the 3 nitrogen of cytosine, and the 6 oxygen of guanine-may also be alkylated to a lesser degree, as are the phosphate atom of the DNA chains and the proteins associated with DNA.Structure of nitrogen mustards. 3D structure of nitrogen mustard and uracil nitrogen mustardAlkylating Mechanism of Mechlorethamine With Guanine Base:Efforts to modify the chemical structure of mechlorethamine to achieve greater selectivity for neoplastic tissues led to the development of cyclophosphamide. After studies of the pharmacological activity of cyclophosphamide, clinical investigations by European workers demonstrated its effectiveness in selected malignant neoplasms.Cyclophosphamide is a classical example of the role of the host metabolism in the activation of an alkylating agent and is one or the most widely used agents of this class. The original rationale that guided its molecular design was twofold. First, if a cyclic phosphamide group replaced the N-methyl of mechlorethamine, the compound might be relatively inert, presumably because the bis-(2-chloroethyl) group of the molecule could not ionize until the cyclic phosphamide was cleaved at the phosphorous-nitrogen linkage. Second, it was hoped that neplastic tissues might posses phosphatase of phosphamidase activity capable of accomplishing this cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. In accord with these predictions, cyclophosphamide displays only weak cytotoxic, mutagenic, or alkylating activity and is relatively stable in aqueous solution. However, when administered to experimental animals or patients bearing susceptible tumors, marked chemotherapeutic effects, as well as mutagenicity and cancinogenicity, are seen. Although a definite role for phosphatases of phosphamidases in the mechanism of action of cyclophospamide has not yet been demonstrated, it is clearly established that the drug initially undergoes metabolic activation be the cytochrome P-450 mixed-function oxidase system of the liver, with subsequent transport of the activated intermediate to sites of action. Thus, a crucial factor in the structure-activity relationship of cyclophosphamide concerns its capacity to undergo metabolic activation in the liver, rather than to alkylated malignant cells directly. it also appears that the selectivity of cyclophosphamide against certain malignant tissues may result in part from the capacity of normal tissues, such as liver, to protect themselves against cytotoxicity by further degrading the activated intermediates.None of the severe acute CNS manifestations reported with the typical nitrogen mustards has been noted with cyclophosphamide. Nosea and vomiting, however, may occur. Although the general cytotoxic action of this drug is similar to that of other alkylating agents, some notable diferences have been observed. When comapred with mechloroethamine, damage to the megakaryocytes and thrombocytopenia are less common. Another unusual manifestation of selectivity consists in more prominent damage to the hair follicles, resulting frequently in alopecia (baldness). The drug is not a vesicant, and local irritaion does occur.Uracil mustard was synthesized in an unsuccessful attempt to produce an active-site alkylator by linking the bis-(2-chloroethyl) group to the pyrimidine base uracil. Its activity in experimental neoplasms was demonstrated shortly thereafter. No relationship has been demonstrated, however, with the biological function of uracil. Note: side effects of chemotherapy can be treated with marijuanaCancer is a group of diseases characterized by abnormal and uncontrolled cell division. One important approach to antitumor agents is the design of compounds with structures related to those of pyrimidines and purines that are involved in biosynthesis of DNA. These compounds are known as antimetabolites because they interfere with the formation or utilization of a normal cellular metabolite. This interference generally results from the inhibition of an enzyme in the biosynthetic pathway of the metabolite from the incorporation, as a false building block, into vital macromolecules such as proteins or nucleic acids.5-Fluorouracile - Pyrimidine Antagonist Uracil is not a component of DNA. Rather, DNA contains thymine, the methylated analog of uracil. The enzyme thymidylate synthetase is required to catalyze this finishing touch: deoxyuridylate (dUMP) is methylated to deoxythymidylate (dTMP) (see figure below). The methyl donor in this reaction is methylenetetrahydrofolate. Rapidly dividing cells require an abundant supply of deoxythymadylate for the synthesis of DNA. Therefore, the vulnerability of these cells to the inhibition of dTMP synthesis can be exploited in cancer therapy.The rational for 5-fluorouracil, 5-FU, was to block DNA synthesis by inhibiting the biosynthesis of dTMP, by virtue of its close structural analogy to uracil. Fluorine, being the smallest atom that would substitute for hydrogen at the 5' position, was assumed to create the smallest possible molecular perturbation and thus be converted to the nucleotide and be accepted by the reactive site of thymidylate synthetase as a substrate imposter. In fact, this was the case. The van der Waals radius of the F atom (1.35 A) is only slightly larger than that of the H atom (1.20 A). Therefore, 5-fluorouracil is a fluorinated pyrimidine analogue which stops cell proliferation by blocking DNA synthesis and RNA processing.Fluorouracil is converted in vivo into fluorodeoxyuridylate (F-dUMP). This analog of dUMP irreversibly inhibits thymidylate synthase after acting as a normal substrate through part of the catalytic cycle. First a sulfhydryl group of the enzyme adds to C-6 of the bound F-dUMP (see figure below). Methylenetetrahydrofolate then adds to C-5 of this intermediate. In the case of dUMP, a hydride ion of the folate is subsequently shifted to the methylene group, and a proton is taken away from C-5 of the bound nucleotide. However, F+ cannot be abstracted from F-dUMP by the enzyme, and so catalysis is blocked at the stage of the covalent complex formed by F-dUMP, methylenetetrahydrofolate, and the sulfhydryl group of the enzyme. We see here and example of suicide inhibition, in which an enzyme converts a substrate into a reactive inhibitor that immediately inactivates its catalytic activity.Edward B. Walker (Weber State University)Anticancer Drugs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Antidepressants

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Pharmaceuticals/Antidepressants

Antidepressant drugs are used to restore mentally depressed patients to an improved mental status. Depression results from a deficiency of norepinephrine at receptors in the brain. Mechanisms that increase their effective concentration at the receptor sites should alleviate depression. Antidepressant drugs act by one or more of the following stimulation type mechanisms:The tricyclic antidepressants are the most effective drugs presently available for the treatment of depression. These act by increasing the release of norepinephrine. Amphetamine and cocaine can also act in this manner. Imipramine, amitriptylin, and other closely related drugs are among the drugs currently most widely used for the treatment of major depression.The activity of the tricyclic drugs depends on the central ring of seven or eight atoms which confers an angled or twisted conformation. The side chain must have at least 2 carbons although 3 appear to be better. The amine group may be either tertiary or secondary. All tricyclic antidepressants block the re-uptake of norepinephrine at nerve terminals. However, the potency and selectivity for the inhibition of the uptake of norepinephrine, serotonin, and dopamine vary greatly among the agents. The tertiary amine tricyclics seem to inhibit the serotonin uptake pump, whereas the secondary amine ones seem better in switching off the NE pump. For instance, imipramine is a potent and selective blocker of serotonin transport, while desipramine inhibits the uptake of norepinephrine.Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter found in cardiovascular tissue, in endothelial cells, in blood cells, and in the central nervous system. The role of serotonin in neurological function is diverse, and there is little doubt that serotonin is an important CNS neurotransmitter. Although some of the serotonin is metabolized by monoamine oxidase, most of the serotonin released into the post-synaptic space is removed by the neuron through a re-uptake mechanism inhibited by the tricyclic antidepressants and the newer, more selective antidepressant re uptake inhibitors such as fluoxetine and sertraline.In recent years, selective serotonin reuptake inhibitors have been introduced for the treatment of depression. Prozac is the most famous drug in this class. Clomiprimine, fluoxetine (Prozac), sertraline and paroxetine selectively block the re uptake of serotonin, thereby increasing the levels of serotonin in the central nervous system. Note the similarities and differences between the tricyclic antidepressants and the selective serotonin re uptake inhibitors. Clomipramine has been useful in the treatment of obsessive-compulsive disorders. Monoamine oxidase (MAO) causes the oxidative deamination of norephinephrine, serotonin, and other amines. This oxidation is the method of reducing the concentration of the neurotransmitter after it has sent the signal at the receptor site. A drug which inhibits this enzyme has the effect of increasing the concentration of the norepinephrine which in turn causes a stimulation effect. Most MAO inhibitors are hydrazine derivatives. Hydrazine is highly reactive and may form a strong covalent bond with MAO with consequent inhibition for up to 5 days.These drugs are less effective and produce more side effects than the tricyclic antidepressants. For example, they lower blood pressure and were at one time used to treat hypertension. Their use in psychiatry has also become very limited as the tricyclic antidepressants have come to dominate the treatment of depression and allied conditions. Thus, MAOIs are used most often when tricyclic antidepressants give unsatisfactory results.Phenelzine is the hydrazine analog of phenylethylamine, a substrate of MAO. This and several other MAOIs, such as isocarboxazide, are structurally related to amphetamine and were synthesized in an attempt to enhance central stimulant properties.Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual ChembookAntidepressants is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Antihistamines and Local Anesthetics

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Medicinal_Chemistry/Antihistamines_and_Local_Anesthetics

Histamine is 2-(4-imidazolyl)ethylamine and is a hydrophilic molecule comprised of an imadazole ring and an amino group connected by two methylene groups. It arises in vivo by decarboxylation of the amino acid histadine.Histamine is concentrated in mast cells, cells whose function is essentially to release histamine and immunoglobins when tissue damage occurs. They are especially numerous in parts of the body that are injured often, such as the fingers and toes, or which enjoy frequent contact with the environment, such as the mucosa of the lips, nose, etc. Histamine is also a neurotransmitter in the CNS and a typical problem with some antihistamines is drowsiness. The effort has been to produce compounds that do not enter the brain very well.There are many drugs with histamine-like properties, and most contain the following fragment:Histamine contracts many smooth muscles, such as those of the bronchi and gut, but powerfully relaxes others, including those of fine blood vessels. It is also a very potent stimulus to gastric acid production. Effects attributable to these actions dominate the overall response to the drug; however, there are several others, of which edema formation and stimulation of sensory nerve endings are perhaps the most familiar. Some of these effects as bronchoconstriction and contraction of the gut, are mediated by one type of histamine receptor, the H1 receptors, which are readily blocked by pyrilamine and other such classical antihistamines, now more properly described as histamine H1-receptor blocking drugs of simply H1 blockers. Other effects, most notably gastric secretion, are completely refractory to such antagonists, involve activation of H2 receptors, and are susceptible to inhibition by the more recently developed histamine H2-receptor blocking drugs. Still others, such as the hypotension resulting from vascular dilation, are mediated by receptors of both H1 and H2 types, since they are annulled only by a combination of H1 and H2 blockers.The two classes of histamine receptors also reveal themselves by differential responses to various histamine-like agonists. Thus, 2-methylhistamine preferentially elicits responses mediated by H1 receptors, whereas 4-methylhistamine has corresponingly preferential effect mediated through H2 receptors. These conpounds are representatives of two classes of histtamin-like dtugs, the H1-agonists and H2-agonists.All of the available antagonists are reversable, competative inhibitors of the actions of histamine. The structure of almost all of the "classic" antihistamines have a tertiary amino group linked by two- or three-atom chain to two aromatic substituens and confrom to the general formula shown below, where Ar is aryl and X is a nitrogen or a carbon aton or a C-O- ether linkage. Two common examples of H1 antagonists are shown below.H1-blocking drugs have an established and valued place in the symptomatic treatment of various immediate hypersensitivity reactions, in which their usefulness is attributable to their antagonism of endogenously released histamine, one of several autoacids that elicit allergic response. In addition, the central properties of some of the series are of considerable therapeutic value in suppressing motion sickness.In treating diseases of allergy, the effect of antihistamines is purely palliative and confined to the suppression in varying degree of symptoms attributable to the pharmacological activity of histamine released by the antigen-antibody reaction. The drugs do not diminish the intensity of this reaction, which is the root cause of the various hypersensitivity diseases. This limitation must be clearly recognized. In bronchial asthma, histamine blockers are singularly ineffectual. The have no role in the therapy of severe attacks in which chief reliance must be placed on epinephrine, isoproterenol, and theophylline. Equally, in the treat5ment of systemic anaphylaxis, in which autoacids other than histamine are again important, the mainstay of therapy is once more epinephrine, with histamine antagonists having only a subordinate and adjuvant role.Other allergies of the respiratory tract are more amenable to therapy with H1 blockers. The best results are obtained in seasonal rhinitis (hay fever) and conjunctivitis, in which these drugs relieve the sneezing, rhinorrhea, and itching of the eyes, nose and throat.The H2 blockers are reversible, competitive antagonists of the actions of histamine on H2 receptors. They are highly selective in their action and are highly selective in their action and are virtually without effect on H1 receptors. The most prominent of the effects of histamine that are mediated by H2 receptors is stimulation of gastric acid secretion, and it is the ability of the H2 blockers to inhibit this effect that explains much of their importance. Despite the widespread distribution of H2 receptors in the body, H2 blockers interfere remarkably little with physiological function other than gastric secretion, implying that extragastric H2 receptors are of minor physiological importanceH2 blockers are used in treatment of peptic ulcer disease PUD; a disease in which ulceration occurs in the lower esophagus, stomach, duodenum, or jejunum. The most prominent symptom is gnawing pain that is relieved by food and alkali, but worsened by alcohol and condiments. The proximate cause of PUD is gastric acid hypersecretion.The synthesis of H2 antagonists was acheived by stepwise modifications of the histamine molecule, which resulted, some 200 compounds later, in the first highly effective drug with potent H2-blocking activity, burimamide. This, like later compounds, retained the imidazole ring of histamine byt possessed a much bulkier side chain. Cimetidine, the first H2 blocker to be introduced for general clinical use, won rapid acceptance for the treatment of ulcers and other gastric hypersecretory conditions and soon became one of the most widely prescribed of all drugs. this success led to the synthesis of numerous congeners. Some of the more popular drugs are shown below.The synthesis of rantadine is not difficult. The figure below shows the three steps of its synthesis from common starting chemicals.The parietal cells secrete acid by means of a membrane pump, identified as an H+, K+-ATPase, that exchanges hydrogen ions for potassium ions. By analogy with the familiar Na+, K+-ATPase, whose function can be inhibited by digitalis, this proton pump can likewise by inhibited by a newly discovered family. Omeprazole is the prototypical "acid pump" inhibitor which was allowed for clinical use in 1989. Its effects on gastric acid reduction are profound, showing a greater decrease of daily acid secretion than is obtained with four cimetidine given four times a day.It has been demonstrated in vitro that under acid conditions as high as 0.5M, HCl, omeprazole cyclized reversibly to a spiro-dyhydroimidazole intermediate (see figure below), which opens to sulfenic acid (not isolated). Cyclization, by the loss of H2O leads to a cyclic sulfenamide that was isolated and identified. Treatment of the sulfenamide with mercaptoehanol (HSCH2CH2OH) opened the ring to produce the predicted disylfide adduct shown. Since these conditions simulate the gastric environment and H+, K+ATPase was known to have an essential -SH group, it has been proposed that the sulfenamide produced from omeprazole is the chemical species that forms a covalent drug-enzyme complex with H+, K-ATPase in the acid compartment of the parietal cell, thereby blocking \(\ce{H^{+}}\) release.Cromolyn sodium, the disodium salt of 1,3-bis(2-carboxychromone-5-yloxy)-2-hydroxypropane, has the following structure:Cromolyn does not relax bronchial or other smooth muscle. Nor does it inhibit significantly responses to these muscles to any of a variety of pharmacological spasmogens. It does, however, inhibit the release of histamine and other autocoids (including leukotrienes) from human lung during allergic responses mediated by IgE antibodies and thereby the stimulus for bronchospasm. Inhibition of the liberation of leukotrienes is particularly important in allergic bronchial asthma, where these products appear to be the principal cause of bronchoconstriction. Cromolyn acts on the pulmonary mast cells for the immediate hypersensitivity reaction. Cromolyn does not inhibit the binding of IgE to mast cells nor the interaction between cell-bound IgE and specific antigen; rather, it suppresses the secretory response to this reaction.Cromolyn sodium is insufflated into the lings by a special device as a micronized powder. The drug is strictly prophylactic; it will not abort an asthmatic attack in progress.The first local anesthetic to be discovered was cocaine, an alkaloid contained in large amounts in the leaves of Erythroxylon coca, a shrub growing in the Andes Mountains. Over 9 million kilograms of these leaves are consumed annually by the 2 million inhabitants of the highlands of Peru, who chew or suck the leaves for the sense of wellbeing it produces. Local anesthetics are drugs that block nerve conduction when applied locally to nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. For example, when they are applied to the motor cortex impulse transmission from that area stops, and when they are injected into the skin they prevent the initiation and the transmission of sensory impulses. A local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. The great practical advantage of the local anesthetic is that their action is reversible: their use is followed by complete recovery in nerve function with no evidence of structural damage to nerve fibers of cells.The structures some of the typical anesthetics are shown below.These structures contain hydrophilic and hydrophobic domains that are separated by an intermediate alkyl chain. Linkage of these two domains is of either the ester or amide type. the ester link is important because this bond is readily hydrolyzed during metabolic degradation and inactivation in the body. Procaine, for example, can be divided into three main portions: the aromatic acid (para-aminobenzoic), the alcohol (ethanol), and the tertiary amino group (diethylamino). Changes in any part of the molecule alter the anesthetic potency and the toxicity of the compound. Increasing the length of the alcohol group leads to a greater anesthetic potency. It also leads to an increase in toxicity. Local anesthetics prevent the generation and the conduction of the nerve impulse. Their site of action is the cell membrane. Local anesthetic and other classes of agents (e.g., alcohols and barbiturates) block conduction by decreasing or preventing the large transient increase in the permeability of the membrane to sodium ions that is produced by a slight depolarization of the membrane. As anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually increases and the safety factor for conduction decreases; when this action is sufficiently well developed, block of conduction is produced.The local anesthetics also reduce the permeability of resting nerve to potassium as well as to sodium ions. Since changes in permeability to potassium require higher concentration of local anesthetic, blockade of conduction is not accompanied by any large or consistent change in the resting potential.All the commonly used local anesthetics contain a tertiary or secondary nitrogen atom and, therefore, can exist either as the uncharged tertiary of secondary amine or as the positively charged substituted ammonium cation, depending on the dissociation content of the compound and the pH of the solutions. The pKa of a typical local anesthetic lies between 8.0 and 9.0, so that only 5 to 20% will be protonated at the pH of the tissues. this fraction, although small, is important because the drug usually has to diffuse through connective tissue and other cellular membranes to reach its site of action, and it is generally agreed that it can do so only in the form of the uncharged amine. Once the anesthetic has reached the nerve, the form of the molecule active in nerve fibers is the cation which combines with some receptor in the membreane to prevent the generationof an action potential.Edward B. Walker (Weber State University)Antihistamines and Local Anesthetics is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Antimicrobial Drugs

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Medicinal_Chemistry/Antimicrobial_Drugs

The modern era of the chemotherapy of infection started with the clinical use of sulfanilamide in 1936. The "golden age" of antimicrobial therapy began with the production of penicillin in 1941, when this compound was mass-produced and first made available for limited clinical trial. More than 30% of all hospitalized patients now receive one or more courses of therapy with antibiotics, and millions of potentially fatal infections have been cured. However, at the same time, these pharmaceutical agents have become among the most misused of those available to the practicing physician. One result of widespread use of antimicrobial agents has been the emergence of antibiotic-resistant pathogens, which in turn has created an ever-increasing need for new drugs. Many of these agents have also contributed significantly to the rising costs of medical care.An antibiotic is any substance produced by a microorganism that is excreted to harm or kill another microorganism. Technically, antibiotics are microbial or fungal products. But these substances can be synthesized and mass produced in the laboratory to use against harmful microorganisms in the environment. Thus, the synthetic chemist has added greatly to our therapeutic armamentarium. Synthetic drugs such as isonaizid and theambutol represent important contributions for the treatment of tuberculosis. While many such antimicrobial agents are not properly termed antibiotics, since they are not produced by living organisms, little distinction should now be made between compounds of natural and synthetic origin.Antibiotics can further be grouped under the broader heading of chemotherapuetic agents, chemical agents used to treat disease. Good chemotherapuetic agents are able to kill or inhibit the target pathogen without too much damage to the host organism. The basis for this selective toxicity lies in the differences between prokaryotic cells of microorganisms and our own eukaryotic cells. The prokaryotic cells of microorganisms differ in a number of ways from eukaryotic cells, such as absence of cell walls, different size of ribosomes, and details of metabolism. Thus, the goal of antibiotic therapy is to choose or design drugs that target these differences in host and pathogen cells.3-D structure of amoxicillinAlexander Fleming loved to play, both in the laboratory and out. He always loved snooker and golf and had many whimsical variants on the rules. In the lab he made "germ paintings," in which he would draw with his culture loop using spores of highly pigmented bacteria, which were invisible when he made the painting, but when cultured developed into brightly colored scenes. He followed what Max Delbruck would later call the "principle of limited sloppiness." Fleming abhorred a tidy, meticulous lab; he left culture dishes lying around for weeks and would often discover interesting things in them. Though the story has been told in many sometimes conflicting ways, something like this resulted in the discovery of penicillin. He seems to have left a culture dish lying on the lab bench and then gone away on vacation. When he returned a few spores of an unusual mold had germinated on the plate. When he cultured the bacteria on the plate he found that they grew up to within a few centimeters of the mold, but there were killed. A crude extract of the mold was then shown to have antibacterial properties. Fleming made this discovery in 1928 and by 1929 had named it penicillin (he was told by a colleague that the mold was a type of Penicillium and "penicillozyme" must have seemed cumbersome). Fleming continued to use penicillin in his lab but not with any great enthusiasm and certainly not to the exclusion of many other projects. He never developed it into a clinically useful compound, though in 1929 he suggested that it might have important clinical applications. Because he was a bacteriologist and not a chemist, Fleming did not attempt to purify penicillin. He seems to have run into a dead end with penicillin and so during the 1930s, though he kept it in his lab, he did not do much with it. In the late 1930s Australian Howard Florey came to London to work with Charles Sherrington. He worked on lysozyme for a while and then became interested in penicillin. It was Florey, with Chain and other of his group that developed penicillin into a clinical antibiotic. They did this during 1940-41. Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology for Medicine. Fleming became world-famous for penicillin, and was rightly acknowledged as the father of modern antibiotics, but Florey was just as rightly miffed at being denied much of the credit for creating the powerful medical tool we now know. Evidence does not suggest that Fleming deliberately denied Florey his due credit, but Fleming's peculiar, dry sense of humor seems to have caused him not to deny even the wildest attributions to him.Cephalosporins are the second major group of b-lactam antibiotics. They differ from penicillins by having the b-lactam ring fused to a dihydrothiazine ring rather than a thiazolidine. The other difference, which is more significant from a medicinal chemistry stand point, is the existence of a functional group (R) at position 3 of the fused ring system. This now allows for molecular variations to be introduced at the 7-NH2 group, as in the penicillins, as well as to effect changes in properties by diversifying the moieties at position 3.The first member of the newer series of b-lactams was isolated in 1956 from extracts of Cephalosporium acremonium, a sewer fungus. This species actually produced several antibiotics: cephalosporin C, cephalosporins P1 - P5 and penicillin N. This was also true with Fleming's Penicillium notatum. However, that was not discovered until research on the chemistry of penicillin was worked on. Cephalosporin has also been identified from other fungi such as Emericellopsis and Paecilomyces, two genera that are morphologically similar to Penicillium. Like penicillin, cephalosporins are valuable because of their low toxicity and their broad spectrum of action against various diseases. In this way, cephalosporin is very similar to penicillin. Cephalosporins are one of the most widely used antibiotics, and economically speaking, has about 29% of the antibiotic market. The cephalosporins are possibly the single most important group of antibiotics today and are equal in importance to penicillin. The structure and mode of action of the cephalosporins are similar to that of penicillin. They affect bacterial growth by inhibiting cell wall synthesis, in Gram-positive and -negative bacteria.Mechanism of ActionPenicillin consists of a thiolidine ring fused to a b-lactam ring, to which a variable R group is attached by a peptide bond. This structure can undergo a variety of rearrangements, which accounts for the instability first encountered by Flemming. In particular, the b-lactam ring is very labile.In 1957, it was shown that bacteria ordinarily susceptible to penicillin could be grown in its presence if a hypertonic medium were used. The organisms obtained this way are devoid of a cell wall and consequently lyse when transferred to a normal medium. Hence it was inferred that penicillin interferes with the synthesis of the bacterial cell wall. The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked lattice work structure, which prevents bacteria from bursting from their high internal osmotic pressure. The peptidoglycan is composed of glycan chains, which are linear strands of alternating pyranoside residues of two amino sugars (N-acetylgucosamine and N-acetylmuramic acid), that are cross-linked by peptide chains. In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick, but it is only 1 or 2 molecules thick in gram-negative bacteria.In 1965, it was deduced that penicillin blocks the last step in cell wall synthesis, namely the cross-linking of different peptioglycan strands. This cross-linking is accomplished by a transpeptidation reaction that occurs outside the cell membrane. The transpeptidase itself, called glycopeptide transpeptidase, is membrane bound. In the formation of the cell wall of Staphylococcus aureus, the transpeptidase normally forms an acyl-enzyme intermediate with the penultimate D-analine residue of the D-Ala-D-Ala-peptide. This covalent acyl-enzyme intermediate then reacts with the amino group of the terminal glycine in another peptide to form the cross-link (see figure below). Therefore, the end result is that the amino group at one end of a pentaglycine chain attacks the peptide bond between two D-analine residues in another peptide unit, a peptide bond is formed between glycine and one of the D-alanine residues, and the other D-alanine residues is released. It should be noted that bacteria cell walls are unique in containing D amino acids, which form cross-links by a different mechanism from that used to synthesize proteins.Penicillin mimics the D-Ala-D-Ala moiety of the normal substrate and is welcomed into the active site of the transpeptidase. Bound penicillin then forms a covalent bond with a serine residue at the active site of the enzyme. This penicilloyl-transpeptidase does not further react and the enzyme is irreversibly inhibited (see figure below).The reason penicillin is so effective in inhibiting glycopeptide transferase is the four-membered b-lactam ring is strained, which makes it highly reactive. Also, the conformation of this part of penicillin is probably very similar to that of the transition state of the normal substrate, a species that interacts strongly with the enzyme.Because of the high use of penicillin, some bacteria have developed resistance by producing molecules that can disable penicillin. Penicillinase is an enzyme produced by certain penicillin-resistant bacteria which reacts irreversibly with the b-lactam ring. Scientists have responded with other drugs that inturn react and disable penicillinase. One such drug is clavulanic acid. This compound irreversibly binds to penicillinase and prevent the enzyme from working. Therefore, sometimes clavulanic acid is given along with one of the semi-synthetic penicillins.Erythromycin is an orally effective antibiotic discovered in 1952 in the metabolic products of a strain of Streptocyces erythreus, originally obtained from a soil sample collected in the Philippine Archepelago. Erythromycin is one of the macrolide antibiotics, so named because they contain a many-membered lactone ring to which are attached one or more deoxy sugars. It is a white crystalline compound, soluble in water to the extent of 2 mg/ml. the structuras formula of erythromycine is a follows:Erythromycin-A has a 14-membered macrolide ring, to which two sugars are attached: desosamine on carbon 5, and cladinose on carbon 3.Crystal ImageErythromycin may be either bacteriostatic or bactericidal, depending on the microorganism and the concentration of the drug. The bactericidal activity is greatest against a small number of rapidly dividing microorganisms and increases markedly as the pH of the medium is raised over the range of 5.5 to 8.5. the antibiotic is most effective in vitro against gram positive cocci such as Strep. pyogens and Strep. Pneumoniae. Resistant strains of these bacteria are rare and are usually isolated from populations of people who have been recently exposed to macrolide antibiotic. For example, in 1979, only 5% of group-A streptococcal strains isolated in Oklahoma were resistant to erythromycin, but 60% of such strains were found to be resistant in Japan. the difference likely reflects the wide use of erythromycin in Japan for respiratory infections.Mechanism of ActionErythromycin and other macrolide antibiotics inhibit protein synthesis by binding to 50 S ribosomal subunits of sensitive microorganisms. (Humans do not have 50 S ribosomal subunits, but have ribosomes composed of 40 S and 60 S subunits). Certain resistant microorganisms with mutational changes in components of this subunit of the ribosome fail to bind the drug. The association between erythromycin and the ribosome is reversible and takes place only when the 50 S subunit is free from tRNA molecules bearing nascent peptide chains. The production of small peptides goes on normally in the presence of the antibiotic, but that of highly polymerized homopeptides is suppressed. Gram-positive bacteria accumulate about 100 times more erythromycin than do gram-negative microorganisms. The nonionized from of the drug is considerably more permeable to cells, and this probably explains the increased antimicrobial activity that is observed in alkaline pH.TetracyclineThe development of the tetracycline antibiotics was the result of a systematic screening of soil specimens collected from many parts of the world for antibiotic-producing microorganisms. The first of these compounds, chlortetracycline, was introduced in 1948. Soon after there initial development, the tetracyclines were found to be highly effective against rickettsiae, a number of gram-positive and gram-negative bacteria, and the agents responsible for conjunctivitis, and psittacosis, and hence became known as "broad spectrum" antibiotics. They are also effective to agents that exert their effects on the bacterial cell wall, such as rickettsiae, Chlamydia, and amebae.ChlortetracyclineIn vitro, tetracycline drugs are primarily bacteriostatic and only multiplying microorganisms are affected. These drugs are closely related bacteriostatic antibiotics, similar in antibacterial spectrum and toxicity. The site of action of tetracyclines is the 30 S subunit of the ribosome, but at least two processes appear to be required for these antibiotics to gain access to the ribosomes of gram-negative bacteria. The first is passive diffusion through hydrophobic pores in the outer cell membrane. The second process involves an active transport system that pumps all tetracyclines through the inner cytoplasmic membrane. Although permeation of these drugs into gram-positive bacteria is less will understood, it too requires an active transport system. Once the tetracyclines gain access to the bacteria cell, they inhibit protein synthesis and bind specifically to 30 S ribosomes. They appear to prevent access of aminoacyl tRNA to the acceptor site on the mRNA-ribosome complex. This prevents the addition of amino acids to the growing peptide chain. Only a small portion of the drug is irreversibly bound, and the inhibitory effects of the tetracyclines can be reversed by washing. Therefore, it is probable that the reversibly bound antibiotic is responsible for the antibacterial action. These compounds also impair protein synthesis in mammalian cells at high concentrations; however the host cells lack the active transport system found in bacteria.Tetracycline-resistant strains of pneumococci account for about 5% of isolates from pneumococcal pneumonia patients. Infections due to Group A beta-hemolytic streptococci should not be treated with a tetracycline, since as many as 25% of the organisms may be resistant when tested in vitro. Serious staphylococcal disease is also not a primary indication for tetracyclines. Bacterial resistance to one tetracycline is generally accompanied by cross-resistance to the others. Pharmacology The tetracyclines are variably absorbed after oral administration. Food interferes with absorption of tetracyclines, with the exception of doxycycline and minocycline. Absorption of tetracyclines is decreased in the presence of antacids containing aluminum, Ca, and Mg, and in preparations containing iron. The half-lives in plasma are about 8 h for oxytetracycline and tetracycline; 13 h for demeclocycline and methacycline; and 16 to 20 h for doxycycline and minocycline. Tetracyclines penetrate into most tissues and body fluids. However, CSF levels are not reliably therapeutic. Minocycline, because of its high lipid solubility, is the only tetracycline that penetrates into tears and saliva in levels high enough to eradicate the meningococcal carrier state. All tetracyclines, except doxycycline, are excreted primarily in the urine by glomerular filtration, and their blood levels increase in the presence of renal insufficiency. Doxycycline is excreted mainly in the feces. All tetracyclines are partially excreted in bile, resulting in high biliary levels. They are then partially reabsorbed.The sulfonamides are synthetic bacteriostatic antimicrobial agents with a wide spectrum encompassing most gram-positive and many gram-negative organisms. These drugs were the first effective chemotherapeutic agents to be employed systematically for the prevention and cure of bacterial infections in man. The considerable medical and public health importance of their discovery and their subsequent widespread use were quickly reflected in the sharp decline in morbidity and mortality figures for the treatable infectious decease. Before penicillin became generally available, the sulfonamides were the mainstay of antibacterial chemotherapy. While the advent of antibiotics has diminished the usefulness of the sulfonamides, they continue to occupy an important, although relatively small, place in the therapeutic armamentarium of the physician.Sulfonimides are structural analogs and competitive antagonists of para-aminobenzoic acid (PABA), and thus prevent normal bacterial utilization of PABA for the synthesis of the vitamin folic acid. (The role of folic acid in RNA synthesis was already discussed in Anti Cancer Drugs). More specifically, sulfonamides are competitive inhibitors of the bacterial enzyme sulfihydropteroate synthase, which is responsible for the conversion of PABA into dihydrofolic acid, the immediate precursor of folic acid. Sensitive microorganisms are those that must synthesis their own folic acid; bacteria that can utilize preformed folic acid are not affected. Bacteriostasis induced by sulfonamides is counteracted by PABA competitively. Sulfonamides do not affect mamalian cells by this mechanism, since they require preformed folic acid and cannot synthesis it.Pharmacology Most sulfonamides are readily absorbed orally, the small intestine being the major site of absorption. Parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. CSF levels are effective in meningeal infections, but sulfonamides are rarely used for this indication. When given in pregnancy, high levels are achieved in the fetus. Sulfonamides are loosely and reversibly bound in varying degrees to serum albumin. Since the bound sulfonamide is inactive and nondiffusible, the degree of binding can affect antibacterial effectiveness, distribution, and excretion. The antibacterial action is inhibited by pus. The sulfonamides are metabolized mainly by the liver to acetylated forms and glucuronides, both therapeutically inactive. Excretion is primarily renal by glomerular filtration with minimal tubular secretion or reabsorption. The relative insolubility of most sulfonamides, especially their acetylated metabolites, may cause precipitation in the renal tubules. The more soluble analogs, such as sulfisoxazole and sulfamethoxazole, should be chosen for systemic therapy, and the patient must be well hydrated. To avoid crystalluria and renal damage, fluid intake should be sufficient to produce a urinary output of 1200 to 1500 mL/day. Sulfonamides should not be used in renal insufficiency.Chloroquine is one of the cheif agents for the chemotherapy of malaria. Although chlorouqine causes a number of effects that singly or in combination may relate to its promary mechanism of plasmodicidal action, this process is not yet shown. From early work, it has been found that chloroquine inhibits the incorporation of phosphate into RNA and DNA. Later it was shown that chloroquine combines strongly with double-stranded DNA. The drug is also reported to inhibit DNA polymerase activity markedly by combing with the DNA primer.A common misuse of these agents is in infections that have been proven to be untreatable. The vast majority of the diseases due to the true viruses will not respond to any of the presently available anti-infective compounds. Thus, the antimicrobial therapy of measles, chickenpox, mumps, and at least 90% of infections of the upper respiratory tract is totally ineffective and, therefore, worse than uselessFever of undetermined etiology may be of two types: one that is present for only a few days to a week and another that persists for an extended period. Both of these are frequently treated with antimicrobial agents. Most instances of pyrexia of short duration, in the absence of localizing signs, are probably associated with undefined viral infections, often of the upper respiratory tract, and do not respond to antibiotics. In the bulk of these cases, defervescence takes place spontaneously within a week or less. Studies of prolonged fever have shown that three common infectious causes are tuberculosis, often of the disseminated variety, hidden pyogenic intraabdominal abscess and infectious endocarditis. Also, the so-called collagen disorders and various neoplasms, especially lymphoma are frequently responsible for prolonged and significant degrees of fever. Various types of cancer, metabolic disorders, hepatitis, asymptomatic regional enteritis, atypical rheumatoid arthritis, and a number of other noninfectious disorders may present themselves as cases of fever of unknown etiology. The most rational approach to the problem of fever of unknown origin is not one that concentrates of the elevated temperature alone but one that involves a thorough search for its cause. The patient should not be unnecessarily exposed to chemotherapy in the hope that, if an agent is not effective, another one or combination of drugs will be helpful.Because of misuse of antibiotics many strains of bacteria have become resistant to the effects of these drugs. Here are some examples of resistance that has occurred in staphylococcus species:Edward B. Walker (Weber State University)Antimicrobial Drugs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Applications of Lipids

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Lipids/Applications_of_Lipids

Fats and lipids are important because they serve as energy source, as well as a storage for energy in the form of fat cells. They also have a major cellular function as structural components in cell membranes. These membranes in association with carbohydrates and proteins regulate the flow of water, ions, and other molecules into and out of the cells. Hormone steroids and prostaglandins are chemical messengers between body tissues. Vitamins A, D, E, and K are lipid soluble and regulate critical biological processes; other lipids add in vitamin absorption and transportation. Lipids act as a shock absorber to protect vital organs and insulate the body from temperature extremes. Thumbnail: This fluid lipid bilayer cross section is made up entirely of phosphatidylcholine. (Public Domain; Bensaccount). Applications of Lipids is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Barbiturates and Benzodiazepines

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Pharmaceuticals/Barbiturates_and_Benzodiazepines

Hypnotic and sedative drugs are non-selective, general depressants of the central nervous system. If the dose is relatively low, a sedative action results in a reduction in restlessness and emotional tension. A larger dose of the same drug produces a hypnotic sleep inducing effect. As the dosage is increased further, the result is anesthesia or death if the dosage is sufficiently high.The barbiturates once enjoyed a long period of extensive use as sedative-hypnotic drugs; however, except for a few specialized uses, they have been largely replaced by the much safer benzodiazepines. Barbiturates are central nervous system depressants and are similar, in many ways, to the depressant effects of alcohol. To date, there are about 2,500 derivatives of barbituric acid of which only 15 are used medically. The first barbiturate was synthesized from barbituric acid in 1864. The original use of barbiturates was to replace drugs such as opiates, bromides, and alcohol to induce sleep.The hyponotic and sedative effects produced by barbiturates are usually ascribed to their interference of nerve transmission to the cortex. Various theories for the action of barbiturates include: changes in ion movements across the cell membrane; interactions with cholinergic and non cholinergic receptor sites; impairment of biochemical reactions which provide energy; and depression of selected areas of the brain. The structures of the barbiturates can be related to the duration of effective action. Although over 2000 derivatives of barbituric acid have been synthesized only about a dozen are currently used. All of the barbiturates are related to the structure of barbituric acid shown below. The duration of effect depends mainly on the alkyl groups attached to carbon # 5 which confer lipid solubility to the drug. The duration of effective action decreases as the total number of carbons at C # 5 increases. To be more specific, a long effect is achieved by a short chain and/or phenyl group. A short duration effect occurs when there are the most carbons and branches in the alkyl chainsThe term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B). However, since all of the important benzodiazepines contain a aryl substituent ring C) and a 1, 4-diazepine ring, the term has come to mean the aryl-1,4-benzodiazepines. There are several useful benzodiazepines available: chlordiazepoxide (Librium) and diazapam (Valium).The actions of benzodiazepines are a result of increased activation of receptors by gamma-aminobutyric acid (GABA). Benzodiazepine receptors are located on the alpha subunit of the GABA receptor located almost exclusively on postsynaptic nerve endings in the CNS (especially cerebral cortex). Benzodiazepines enhance the GABA transmitter in the opening of postsynaptic chloride channels which leads to hyperpolarization of cell membranes. That is, they "bend" the receptor slightly so that GABA molecules attach to and activate their receptors more effectively and more often.Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual ChembookBarbiturates and Benzodiazepines is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Basic Aspects of Drug Activity

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While there are several types of exceptions, the effects of most drugs result from their interaction with functional macromolecular components of the organism. Such interaction alters the function of the pertinent cellular component and thereby initiates the series of biochemical and physiological changes that are characteristic of the response to the drug. The term receptor is used to denote the component of the organism with which the chemical agent interacts. By virtue of interactions with such receptors, drugs do not create effects but merely modulate ongoing function. Thus, drugs cannot impart a new function to a cell. four stereo isomers. Interaction with biological receptors can differ greatly between two enantomers, even to the point of no binding. There are numerous examples among drug molecules where only one isomer exhibits the desired pharmacology. Some isomers may even cause side effects or entirely different effects than its mirror image.Ephedrine has two chiral centers and four isomers:Different isomers can be used in different cases depending on the desired effect. Clinically, D(-) ephedrine is used to a large extent as an anti-asthmatic and, formerly, as a presser amine to restore low blood pressure as a result of trauma. L(+) pseudo-ephedrine is used primarily as a nasal decongestant.If the biological receptor has at least three binding sites, the receptor easily can differentiate enantomers (see figures below). The R(-)isomer has three points of interaction and is held in the conformation shown to maximize binding energy, whereas, the S(+)isomer can have only two sites of interaction.It should be noted that the structure of alpha and beta adrenergic receptors are not entirely known. Also we should not forget that there is also enantioselectivity with respect to pharmacokinetics, such as, absorption, distribution, metabolism, and excretion.Cell signaling is the method in which cells communicate between each other in order to coordinate their activities and react to changes in their environments. Cell signaling involves a signal molecule (an agonist) and a specific signal receptor. Agonistic drugs are those which mimick natural signaling molecules and couse similar effects, while antagonists compete or inhibit agonists and hamper their effects.Agonist Drugs. Agonist drugs mimic cell signaling molecules by activating the same receptor sites and causing similar effects. Both are described quantitatively by the same methods. If one assumes that an agonist drug interacts reversibly with its receptor and that the resultant effect is proportional to the number of receptors occupied, the following reaction can be written:\[ \text{Drug (D)} + \text{Receptor (R)} \ce{ <=>[k_1][k_2]} DR \rightarrow \text{Effect}\]This reaction sequence is analogous to the interaction of substrate with enzyme, and the magnitude of effect can be analyzed in a manner similar to that for enzymatic product formation. The application equation is identical in form with the Michaelis-Menten equation:\[ \text{Effect} = \dfrac{(\text{Maximal Effect}) [D]}{K_d+[D]} \label{2}\]where[D] is the concentration of free drug and KD (equal to K2 / K1) is the dissociation constant for the drug-receptor complex. This equation describes a simple rectangular hyperbola . There is no effect at [D] = 0; the effect is half-maximal when [D] = KD, that is when half of the receptors are occupied; the maximal effect is approached asymptotically as [D] increases above KD . Therefore, doubling the dose does not double the drug effect, but creates a less than two-fold consequence. It is frequently convenient to plot the magnitude of effect versus log [D], since a wide range of drug concentrations is easily displayed and a portion of the curve is more linear. In this case, the result is the familiar sigmoidal log dose-effect curve .Equation \ref{2} can be rearranged by taking the reciprocal of both sides. The graph of the resulting equation is called the Lineweaver-Burk plot:\[ \dfrac{1}{\text{Effect}} = \dfrac{K_D}{(\text{Max Effect} [D])} + \dfrac{1}{\text{Max Effect}} \label{3}\]A plot of 1/Effect versus 1/[D] yields a straight line that intersects the Y-axis at 1/(Max. Effect) and that has a slope equal to KD/(Max. Effect). Extrapolation of this line to the X-axis yields the value of -1/KD . Thus, values of \(K_D\) and Max. Effect can be readily calculated from such a plot. This representation is especially useful for analyzing drug antagonism., the intercept on the 1/Effect axis is increased and the new slope, is steeper. In contrast with the Max. Effect, KD is not affected by this kind of inhibition and so the x-intercept is unaltered. Noncompetitive inhibition cannot be overcome by increasing the agonist concentration.Antagonists may thus be classified as acting reversibly or irreversibly. If the antagonist binds at the active site for the agonist, reversible antagonists will be competitive and irreversible antagonists will be noncompetitive. If binding is elsewhere, however, these simple rules do not hold, and any combination is possible.Down load the spreadsheet used to make . Interactions Between DrugsThere are two primary factors contributing to drug interactions. First, many drugs are bound to plasma proteins and this binding serves as a reservoir of inactive drugs. If a second drug displaces a drug already bound to the protein (by competing for the same protein), more of the previously bound drug will be able to pass out of the bloodstream and be available to the receptor and thus a more intense effect may be produced: the displacing drug would increase the effects or the toxicity of the displaced drug.Second, a drug that is metabolized by the liver may induce new enzymes, which can then metabolize any of a variety of new drugs. Thus, an enzyme-inducing drug such as pentobarbital will decrease the activity of other drugs metabolized by the liver by increasing their rates of metabolism. Therefore, a wide variety of factors influence a drug's action in the body, making the use of more than one drug at a time risky, whether they are used separately or mixed in a concoction.Dynamics of drug absorption, distribution and elimination.Pharmacokinetics deals with the absorption, distribution, biotransformation, and excretion of drugs. These factors, coupled with dosage, determine the concentration of a drug at its sites of action and, hence, the intensity of its effects as a function of time. Many basic principles of biochemistry and enzymology and the physical and chemical principles that govern the active and passive transfer and the distribution of substances across biological membranes are readily applied to the understanding of this important aspect of medicinal chemistry.Drug EliminationDrugs are eliminated from the body either unchanged or as metabolites. Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high lipid solubility. Lipid-soluble drugs are thus not readily eliminated until they are metabolized to more polar compounds.The kidney is the most important organ for elimination of drugs and their metabolites. Substances excreted in the feces are mainly unabsorbed orally ingested drugs or metabolites excreted in the bile and not reabsorbed from the intestinal tract. Excretion of drugs in milk is important not because of the amounts eliminated but because the excreted drugs are potential sources of unwanted pharmacological effects in the nursing infant. Pulmonary excretion is important mainly for the elimination of anesthetic gases and vapors: occasionally, small quantities of other drugs of metabolites are excreted by this route.Drug elimination follows first-order kinetics. To illustrate first order kinetics we might consider what would happen if we were instantly inject (with an IV) a person with a drug, collect blood samples at various times and measure the plasma concentrations Cp of the drug. We might see a steady decrease in concentration as the drug is eliminated, as shown in the figure below. If we measure the slope of this curve at a number of times we are actually measuring the rate of change of concentration at each time point. This can be written mathematically as Equation \ref{4}:\[\dfrac{dC_p}{dt} = - k_{el}C_p \label{4}\] where \(k_{el}\) is an elimination constant. Can you make a plot from this equation to calculate Kel? How can this equation be rearranged to determine Kel?If we integrate, we find that the plasma concentration at a given time is Equation \ref{5}:\[ C_p = C_P^o e^{-k_{el}t} \label{5}\]where Cpo is the initial plasma concentration. In the process of deriving this equation we can calculate the half life to be Equation 6:\[t_{1/2} = \dfrac{0.693}{k_{el}}\label{6}\]So far we have considered elimination by excretion into urine only. Usually drugs are eliminated by excretion AND metabolism. Schematically this can be represented as:where ke is the excretion rate constant and km is the metabolism rate constant. Here we have two parallel pathways for elimination although there could be more pathways, ie. excretion by exhalation, in sweat, or as is commonly the case, more than one metabolite. The differential equations for the two components shown in this diagram could be written just as we did above.Apparent Volume of Distribution, VWe can also use the equations above to calculate the plasma concentration at any time when we know kel and Cpo. However, usually we don't know Cpo ahead of time, but we do know the dose. To calculate Cpo we need to know the volume that the drug is distributed into. That is, the apparent volume of the mixing container, the body. This apparent volume of distribution is not a physiological volume. It won't be lower than blood or plasma volume but it can may be much larger than body volume for some drugs. It is a mathematical 'fudge' factor relating the amount of drug in the body and the concentration of drug in the measured compartment, usually plasma. This can be expressed as Equation 7:or Immediately after an intravenous dose is administered, the amount of drug in the body is the dose. Thus we get equation 8:or Some example values for apparent volume of distribution are listed in the table below.The last figure, for digoxin, is much larger than body volume. The drug must be extensively distributed into tissue, leaving low concentrations in the plasma, thus the body as a whole appears to have a large volume, of distribution. Remember, this is not a physiological volume.From Equations 8 and 5 we can produce Equation 9:Here are some Example Calculations* to try.Clearance, CLClearance is the most important concept to be considered when a rational regiment for drug administration is to be designed. The clinician usually wants to maintain steady- state concentrations of a drug within a known therapeutic range. Assuming complete bioavailability, the steady state will be achieved when the rate of drug elimination equals the rate of drug administration in equation 10:Dosing rate = CL*Csswhere CL is clearance and Css is the steady-state concentration of the drug.Clearance can be defined as the volume of plasma which is completely cleared of drug per unit time. The symbol is CL and the units are ml/min, L/hr, i.e. volume per time. Another way of looking at Clearance is to consider the drug being eliminated from the body ONLY via the kidneys. (If we were to also assume that all of the drug that reaches the kidneys is removed from the plasma then we have a situation where the clearance of the drug is equal to the plasma flow rate to the kidneys. All of the plasma reaching the kidneys would be cleared of drug.)The amount cleared by the body per unit time is dU/dt, the rate of elimination (also the rate of excretion in this example). To calculate the volume which contains that amount we can divide by Cp. That is the volume = amount/concentration. As we have defined the term here it is the total body clearance. We have considered that the drug is cleared totally by excretion in urine. Below we will see that the total body clearance can be divided into a clearance due to renal excretion and that due to metabolism.Clearance is a useful term when talking of drug elimination since it can be related to the efficiency of the organs of elimination and blood flow to the organ of elimination. It is useful in investigating mechanisms of elimination and renal or hepatic function in cases of reduced clearance of test substances. Also the units of clearance, volume/time (e.g. ml/min) are easier to visualize, compared with elimination rate constant (units 1/time, e.g. 1/hr).Total body clearance, CL, can be separated into clearance due to renal elimination, CLr and clearance due to metabolism, CLm.CLr = ke * V (renal clearance) and CLm = km * V (metabolic clearance)where these are combined to give equation 13:CL = CLr + CLmEquation 11 can be rearranged to get: thus a plot of dU/dt versus Cp will give a straight line through the origin with a slope equal to the clearance, CL.Pharmacokinetics of Oral AdministrationMost commonly the absorption process of oral administration follows first order kinetics. Even though many oral dosage forms are solids which must dissolve before being absorbed the overall absorption process can often be considered to be a single first order process. At least that's the assumption we will use for now.Schematically this model can be represented as: Where Xg is the amount of drug to be absorbed, Xp is the amount of drug in the body, and ka is the first order absorption rate constant.The differential equation for Xg is Equation 14:This is similar to the equation for after an IV injection.Integrating this we get Equation 15:Xg = Xg0 * e-ka * t = F * Dose * e-ka * twhere F is the fraction of the dose which is absorbed, the bioavailability.For the amount of drug in the body Xp ( = V * Cp), the differential equation is Equation 16:The first term of this equation is ka * Xg which is absorption, and the second term is kel * V * Cp which is elimination.Even without integrating this equation we can get an idea of the plasma concentration time curve.At the start Xg >> V * Cp therefore the value of is positive, the slope will be positive and Cp will increase. With increasing time Xg will decrease, while initially Cp is increasing, therefore there will be a time when ka * Xg = kel * V * Cp. At this time will be zero and there will be a peak in the plasma concentration. At even later times Xg --> 0, and will become negative and Cp will decrease.Now we will integrate the equation. Starting with the differential equation we can substitute Xg = Xg0 *e-ka * t. If we use F * DOSE for Xg0 where F is the fraction of the dose absorbed, the integrated equation for Cp versus time is Equation 17:Notice that the right hand side of this equation (Equation 17) is a constant multiplied by the difference of two exponential terms. A biexponential equation.We can plot Cp as a constant times the difference between two exponential curves. If we plot each exponential separately we get the following: Notice that the difference starts at zero, increases, and finally decreases again. By adding the two lines in the second plot we get the actual plasma concentration. Plotting this difference we get:.We can calculate the plasma concentration at anytime if we know the values of all the parameters of Equation 17.We can also calculate the time of peak concentration using the equation:As an example we could calculate the peak plasma concentration given that F = 0.9, DOSE = 600 mg, ka = 1.0 hr-1, kel = 0.15 hr-1, and V = 30 liter. = 2.23 hour= 21.18 x [ 0.7157 - 0.1075] = 12.9 mg/LAs another example we could consider what would happen with ka = 0.2 hr-1 instead of 1.0 hr-1= 5.75 hour= 72 x (0.4221 - 0.3166) = 7.6 mg/L lower and slower than before.Multiple dosesUsing Equation 17 above we can create a spreadsheet that will describe the effects of multiple doses given at different time intervals (see plot below). Using a graph such as this, we can coordinate drug doses with proper time intervals in order to will keep drug concentrations at there optimum levels..Plot of plasma concentration due to multiple oral doses of a hypothetical drug. The doses are 200 mg every 8 hours; the fraction absorbed was 1.00; the elimination constant is 0.2/hr; the absorption constant is 1.0/hr; and the volume concentration is 30 L.Edward B. Walker (Weber State University)Basic Aspects of Drug Activity is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Carbohydrates Fundamentals

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Carbohydrates, also known as sugars, are found in all living organisms. They are essential to the very source of life (ex. Ribose sugars in DNA and RNA) or sustaining life itself (e.g., Metabolic conversion of carbohydrates into usable biochemical energy, ATP). Another important role of carbohydrates is structural (ex. Cellulose in plants). General names for carbohydrates include sugars, starches, saccharides, and polysaccharides. The term saccharide is derived from the Latin word "sacchararum" from the sweet taste of sugars. The name "carbohydrate" means a "hydrate of carbon." The name derives from the general formula of carbohydrate is Cx(H2O)y - x and y may or may not be equal and range in value from 3 to 12 or more. For example glucose is: C6(H2O)6 or is more commonly written, C6H12O6. Thumbnail: Haworth formula of D-glucose.Carbohydrates Fundamentals is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Cardiovascular Drugs

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Cardiovascular disease constitutes the largest single cause of death in the industrialized countries. As with cancer, which is a distant second in terms of mortality, cardiovascular disease morbidity increases with age, accounting for about two-thirds of all deaths in persons over 75. Even though some diseases affect primarily the heart and other diseases effect the vascular system, they cannot be divorced from each other. This obvious interdependence makes a unified imperative. One of the major diseases, atherosclerosis, affects and ultimately damages the heart, kidneys, and other organs.Hypertension is generally defined as an elevation of systolic and/or arterial blood pressure and a value of 140/90 torr is generally accepted as the upper limit of normotension. Certain risk factors (e.g., hypercholesterolemia, diabetes, smoking, and a family history of vascular disease) in conjunction with hypertension predispose to arteriosclerosis and consequent cardiovascular morbidity. Patient populations with sustained diastolic blood pressures in the range of 105 to 129 torr are unequivocally benefited by effective reduction of blood pressure. The benefits of antihypertensive treatment are the avoidance of accelerated or malignant hypertension, a lower incidence of hypertensive renal failure, and a decrease in the incidence of hemorrhagic stroke and cardiac failure. Only recently has it been demonstrated that aggressive care of patients with mild diastolic hypertension can apparently reduce the incidence of myocardial infarction.b-blockersSince they where introduced in the 1960s, b-adrenergic blocking agents have become the most commonly used drugs for cardiovascular diseases. Propranolol was the first b-blocker to come into wide clinical use, and it remains the most important of these compounds. It is a highly potent, nonselective adrenergic blocking agent with not intrinsic sympathomimetic activity. However, because of its ability to block b receptors in bronchial smooth muscle and skeletal muscle, propranolol interferes with bronchodiation produced by epinephrine and with glycogenolysis, which ordinarily occurs during hypoglycemia. Thus, the drug is usually not used in individuals with asthma and must be used cautiously in diabetics who are receiving insulin. As a consequence, there has been a search for b-blockers that are cardioselective and a number of drugs now have been developed that exhibit some degree of specificity for b1-adrenergic receptors. Metaprolol is a prototype for these more specific drugs.Much of the pharmacology of b-blockers can be deduced from a knowledge of the functions subserved by the involved receptors and the physiological conditions under which they are activated. Thus, b-receptor blockade has little effect on the normal heart with the subject at complete rest, but may have profound effects when sympathetic control of the heart is high, as during exercise. b-blockers decrease heart rate and cardiac output, prolongs mechanical systole, and slightly decreases blood pressure in resting subjects. Peripheral resistance is increased as a result of compensatory sympathetic reflexes, and blood flow to all tissues except the brain is reduced. Some of these drugs also have direct actions on cell membranes, which are commonly described as membrane stabilizing and local anesthetic. The local anesthetic potency of propranolol is about equal to that of lidocaine. b-blockers are effective antihypertensive agents. Chronic treatment of hypertensive patients with b-adrenergic blocking agents results in a slowly developing reduction in blood pressure. Several mechanisms have been proposed for the efficacy of b-blockers in the management of hypertension. Reduction in cardiac output occurs rather promptly after administration of b-blockers. However, the hypotensive effects of b-blockers does not appear as rapidly. The release of renin from the juxtaglumarular apparatus is stimulated by adrenergic agonists, and this effect is blocked by drugs such as propranolol. Also, b-adrenergic agonists are known to increase modestly the release of norepinephrine from adrenergic nerve terminals, which causes vasoconstriction. b-blockers block this effect, and such impairment of the release of norepinephrine following sympathetic nerve stimulation might contribute to the antihypertensive effects of the drugs.a-Adrenergic blocking agents exist in most blood vessels, particularly in coetaneous resistance vessels. Since their stimulation leads to constriction and therefore blood pressure elevation, it stands to reason that blocking such stimulation would lead to a diminution of blood pressure. Phenoxybenzamine binds covalently to the a receptor and produces an irreversible type of blockade. Phentolamine and tolazoline bind reversibly and antagonize the actions of sympathomimetic amines competitively.Rauwofia serpentina is a climbing shrub indigenous of India and neighboring countries. In 1954, it was reported that rauwolfia or reserpine was helpful in the treatment of psychotic patients because it acts centrally to produce characteristic sedation and a state of indifference to environmental stimuli; effects which resemble phenothiazines (discussed in Psychoactive Drugs). Subsequent discovery of the ability of rauwolfia alkaloids and related compounds to deplete biogenic amines from storage sites in the body initiated a great number of investigations directed at elucidating the interaction between these amines and reserpine. There are a number of rauwolfia alkaloids with complex structures. The structure of reserpine is as follows:It is clear that reserpine interferes with intracellular storage of catecholamines, but the amounts of reserpine in tissues are much too small to assume a stoichiometric displacement. Reserpine antagonizes the uptake of norepinephrine by isolated chromaffin granules by inhibiting the ATP-Mg2+-dependent uptake mechanism of the granule membrane. The drug also binds to the vesicular membranes for days, accounting for the irreversibility of the process. Reserpine depletes stores of catecholamines in many organs, including the brain and adrenal medulla, and most of its pharmacological effects have been attributed to this action. Since it is the reuptake and not the release of catecholamines that is inhibited, the existing pool must be fully depleted before antihypertensive effects become apparent. Also,, after administration of relatively large doses, reserpine causes a transient sympathomimetic effect followed by a slowly developing fall in blood pressure frequently associated with bradycardia. For normal doses, reduced concentrations of catecholamines can be measured within a hour after administration of reserpine, and depletion is maximal at 24 hours. Most of the catecholamine is deaminated intraneuronally, and pharmacological effects of the released mediator are minimal unless MAO has been inhibited. The decrease in norepinephrine synthesis induced by reserpine is the block of dopamine uptake into storage granules that contain the enzyme dopamine b-hydroxylase (see norepinephrine synthesis). Furthermore, the increased concentration of free catecholamine presumably feeds back to inhibit tyrosine hydroxylase, since norepinephrine competes with the pterin cofactor for the enzyme.Supersensitivity to catecholamines is observed following chronic administration of reserpine. The site of change is presumably postjunctional and may by due to alterations of the adrenergic receptors. Such adaptive change is usual following chronic deprivation of transmitter.Reserpine is used as an effective antihypertensive agent, particularly when used with other agents such as diuretics. Its low cost, once-daily administration, and minimal change in effect when compliance is erratic make it useful as an agent for long-term treatment of patients with uncomplicated mild hypertension. However, reserpine causes mental depression in 25% of patients.A diuretic is a substance that increases the rate of urine volume output, as the name implies. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most diuretics that are used clinically act by decreasing the rate of sodium reabsorbtion from the nephron tubules, which in turn causes naturesis and this in turn causes diuresis. The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with edema and hypertension.Soon after the introduction of the sulfonamides as antibacterial agents in the 1930s, changes in the electrolyte balance of patients were noted as was systemic acidosis accompanied by an alkalization of the urine due to increased rate of HCO3- excretion. Proposals by several researchers established that inhibition of the enzyme carbonic anhydrase (CA) accounted for the electrolytic imbalances produced. Since the antibacterial sulfonamides were relatively weak inhibitors, a successful search for more potent CA inhibition ensued. Acetazolamide became the first successful drug introduced into clinical use.Among the enormous number of sulfonamides that have been synthesized and tested, acetazolamide has been studied the most extensively as an inhibitor of carbonic anhydrase. The other drugs of this class that are available in the U.S. are dichlorphenamide and methazolamide. There structural formulas are as follows:Mechanism of Action. The kidneys control acid-base balance of the body by excreting either an acidic or a basic urine. The overall mechanism by which the kidneys accomplish this is as follows: Large numbers of bicarbonate ions are filtered continuously into the nephron tubules of the kidneys, and if they are excreted into the urine, this removes base from the blood. On the other hand, large numbers of hydrogen ions are also secreted into the tubular lumen by the tubular epithelial cells, thus removing acid from the blood.Bicarbonate ions enter the tubular lumen of the kidney nephron with the glumerular filtrate. Bicarbonate ions do not readily permeate the luminal membranes of the renal tubular cells; therefore, bicarbonate ions that are filtered by the glomerulus cannot be directly reabsorbed. Instead, bicarbonate is reabsorbed by a special process in which it first combines with hydrogen ions to from H2CO3, which eventually becomes CO2 and H2O.\[\ce{ H^{+} + HCO3 <=> H2CO3 <=> CO2 + H2O}\]This reabsorbption of bicarbonate ions is initiated by a reaction in the tubules between bicarbonate ions filtered at the glomerulus and hydrogen ions secreted by the tubular cells. The H2CO3 formed then dissociates into CO2 and H2O. The CO2 can move easily across the tubular membrane; therefore, it instantly diffuses into the tubular cell, where it recombines with H2O, under the influence of carbonic anhydrase, to generate new a H2CO3 molecule. This H2CO3 in turn dissociates to form bicarbonate ion and hydrogen ion. The hydrogen ions are secreted from the cell into the tubular lumen, by sodium-hydrogen pump, in exchange for sodium. The bicarbonate ions together with the exchanged Na+, then enter the peritubular blood supply. The hydrogen ion, now in the tubular lumen, combines with another bicarbonate ion to form H2CO3, which then again dehydrates to CO2, which reenters the tubular cell. The net result is reabsorbtion of most of the bicarbonate. Some of these concepts can be seen here in an animated nephron (you must have the shockwave plugin to view this). animatedA hydrogen-bonding mechanism that acts competitively explains the action of acetazolamide-like carbonic anhydrase inhibitors that have diuretic properties. Carbonic acid is the normal substrate that fits into a cavity of and complexes with the enzyme carbonic anhydrase. This complex is strongly stabilized by four hydrogen bonds (see figure below). The acetazolamide-like drugs fit into the cavity of the enzyme also effectively bond, presumably to the same four areas by hydrogen bonds (see figure below).Thus these sulfonamide agents competitively prevent the carbonic acid from binding at this site which inhibits the reabsorption of NaHCO3 and H20. More than 99% of the enzyme activity in the kidney must be inhibited before physiological effects become apparent.Following the administration of acetazolamide, the urine volume promptly increases. The urinary excretion of bicarbonate and fixed cation, mostly sodium (also potassium) and the normally acidic pH becomes alkaline. As a result, the concentration of bicarbonate in the extracellular fluid decreases and metabolic acidosis results. The urinary concentration of chloride falls. The presence of carbonic anhydrase in a number of intraocular structure, including the cilliary processes, and the high concentration of bicarbonate in the aqueous humor have focused attention on the role that the enzyme might play in the secretion of aqueous humor. acetazolamide reduces the rate of aqueous humor formation; intaocular pressure in patients with glaucoma is correspondingly reduced.Thiazines and related compounds comprise the most frequently used antihypertensive agents in the United States. They were synthesized as an out growth of studies on carbonic anhydrase inhibitors. Thiazides act directly of the kidney to increase the excretion of sodium chloride and an accompanying volume of water. Also many of these drugs act as corbonic anhydrase inhibitors. At the molecular level, it is unknown how benzothiadiazines inhibit the reuptake of sodium chloride.Angina pectoris, or ischemic heart disease, is the name given to the symptomatic oppressive pain resulting from myocardial ischemia. In simplest terms it results when the oxygen demand of myocardial tissues exceeds the circulatory supply. Once a local anemia due to an obstruction exists, biochemical changes are inevitable. Metabolic products will accumulate in the area, contractility declines, and NE release occurs from sympathetic neurons. The end result is pain. The underlying pathology of typical angina is usually advanced atherosclerosis and stenosis of the coronary vasculature which causes localized oxygen starvation. Episodes are be precipitated by emotional stress or exercise, but they usually cease rapidly with rest or nitroglycerin. In contrast, variant angina is caused by vasospasm of the coronary vessel and may or may not be associated with severe atherosclerosis. Patients with variant angina develop chest pain while at rest.Until recently, many of the drugs used to prevent anginal attacks were no more effective than a placebo. In fact. the use of placebos has been reported to relieve symptoms in as many as 50% of patients with angina pectoris. For over a century, however, nitroglycerin has been known to be useful to prevent or relieve acute anginal attacks. More recently, the efficacy of b-adrenergic antagonists has been established for the long-term prophylaxis of typical angina. In addition, the calcium channel blockers appear to be effective for the treatment of vasospastic angina. While antianginal agents provide only symptomatic treatment, administration of these drugs do appear to decrease the incidence of sudden death associated with myocardial ischemia and infarction.Organic NitratesThe organic nitrates and nitrites are dilators of arterial and venous smooth muscle. The venodilation results in decreased left and right ventricular end-diastolic pressure, which are greater on a percentage basis than is the decrease in systemic arterial pressure. Net systemic vascular resistance is usually relatively unaffected; heart rate is unchanged or slightly increased; and pulmonary vascular resistance is consistently reduced. These drugs correct the inadequacy of myocardial oxygenation by increasing the supply of oxygen to ischemic myocardium by direct dilatation of the coronary vasculature and by decreasing the oxygen demand for oxygen by a reduction in cardiac work. The latter results from the decrease in vascular pressure enabling the heart to pump blood easier.Glyceryl TrinitrateGlyceryl trinitrate, or nitroglycerine, is a dense sweet-smelling oil that is highly explosive. The most utilized dosage form of nitroglycerin has been the sublingual tablet. Buccal absorption is rapid, offering almost instantaneous relief of sufficient duration (<30 min) for the emergency. Nevertheless, because of the valuable properties of nitroglycerin is now known to have in angina pectoralis, continuous blood levels of the drug are desirable. Therefore, different and innovative dosage forms are being developed. Because nitroglycerin is efficiently absorbed through the skin, this has led to the introduction of nitroglycerin skin patches. These patches contain the drug in a form which results in its continuous release. 3-DMechanism of ActionNitric oxide (NO) has been shown to be an important messenger in many signal transduction processes. This free radical gas is naturally produced endogenously from arginine in a complete reaction that is catalyzed by nitric oxide synthetase (NOS).Nitroglycerin, nitrites, and organic nitrates also lead to the formation of the reactive free radical NO and is the basis of their mechanism of action. However, it is not known the exact enzyme that converts these drugs into NO.Nitric oxide diffuses freely across membranes but has a short life, less than a few seconds, because it is highly reactive. Nitric oxide then activates a heme prosthetic group on the enzyme guanylate cyclase in the cell membrane. The heme molecule is, in effect, functioning as an extremely sensitive detector of NO. A portion of the enzyme protrudes to the interior of the cell and causes the formation of cyclic guanosine monophosphate (cGMP), a so-called second messenger. The cGMP in turn has many effects, one of which is to change the degree of phosphorylation of several enzymes that indirectly inhibit contraction. Especially, the pump that pumps calcium ions from the sarcoplasm into the sarcoplasmic reticulum in activated as well as the cell membrane pump that pumps calcium ions out of the cell itself; these effects reduce the intracellular calcium ion concentration, thereby inhibiting contraction.ViagraViagra, an experimental heart medication with a great side effect.More on the Chemistry of ViagraDigitalis is the dried leaf of the foxglove plant, Digitalis purpurea. Seeds and leaves of a number of other species also contain active cardiac principles. The two molecules in digitalis responsible for its pharmacological activity are digoxigenin and digitoxigenin. As you can see from the structures below, these genins are chemically related to sex and adrenocortical hormones.Digitalis has a powerful action of the myocardium that is unrivaled in value for the treatment of heart failure. It is also used to slow the ventricular rate in the presence of atrial fibrillation and flutter. The main pharmacodynamic property of digitalis is its ability to increase the force of myocardial contraction. The beneficial effects of the drug in patients with heart failure - increased cardiac output; decreased heart size. venous pressure, and blood volume; diuresis and relief of edema - are all explained on the basis of increased contractile force, a positive inotropic action.The most important component to the positive inotropic effect of digitalis direct inhibition of the membrane-bound Na+, K+-activated ATPase, which leads to an increase in intracellular [Ca+]. It seems clear that digitalis, in therapeutic concentrations, exerts no direct effect on the contractile proteins or on the interactions between them. Also, it seems most unlikely that the positive inotropic effect of digitalis is due to any action of the cellular mechanisms that provide the chemical energy for contraction. The hydrolysis of ATP by the Na+, K+-ATPase provides the energy for the so-called sodium-potassium pump - the system in the sarcolemma of cardiac fibers that actively extrudes sodium and transports potassium into the fibers. Digitalis drugs bind specifically to the Na+, K+-ATPase, inhibit its enzymatic activity, and impair the active transport of these two monovalent cations. As a result, there is a gradual increase in intracellular [Na+] and a gradual decrease in internal [K+]. These changes are small at therapeutic concentrations of the drug. It is judged to be crucially related to the positive inotropic effect of digitalis. This is so because in cardiac fibers, intracellular Ca2+ is exchanged for extracellular Na+ by a different transmembrane pump. When internal [Na+] is increased because of inhibition of the Na+, K+ pump by digitalis, the exchange of extracellular Na+ for intracellular Ca2+ is diminished, and internal [Ca2+] increases. The probable consequence of this is an increased store of Ca2+ in the sarcoplasmic reticulum and, with each action potential, a greater release of Ca2+ to activate the contractible apparatus.Interactions of Na+, K+-ATPase with its various substrates are complex. Thus binding affinities with ATP, cofactor MG2+, Na+, K+, and a digitalis glycoside are all important to the overall effect. It is now accepted that the digitalis receptor is one or more of the conformations of Na+, K+-ATPase that occur during the ion pump's operation, possibly during a state in which the drug helps to stabilize one of the intermediate states of the enzyme.Evidence suggests that the entire glycoside molecule participates in the proposed drug-receptor interaction. The steric relationship of the lactone ring to the steroid nucleus is absolute. The double bond is also critical since saturation results in an almost total loss of activity. The required stereochemical positioning of rings C and D in relation to each other (cis) and of A and B (cis), and the configuration of the OH at C-14 (between rings C and D) have all been established. The figure below is a highly simplified version of a proposed interaction of the lactone side chain with such a digitalis receptor.It is believed that the polarized carbonyl group, with its electron-rich oxygen, hydrogen bonds to a hydroxyl group on the enzyme's surface, probably to a serine residue, and the carbon atom bonded to the steroid nucleus is attracted to an electron dense site at a secondary location.More Info on DigitalisFrom any viewpoint blood is chemically the most complex tissue in the body. In addition to the multitude of cells and platelets, it contains inorganic ions, various plasma proteins, hormones, lipids, vitamins, a large variety of enzymes, nucleic acid breakdown products, a large number of unknown types of environmentally ingested chemical at varying stages of metabolic conversion, gases, and water. Among these is a group of more than a dozen chemical factors that will cause the blood to coagulate when properly triggered. Hemostasis is the spontaneous arrest of bleeding from damaged vessels. Precapillary vessels contract immediately when cut. Within seconds, thrombocytes are bound to the exposed collagen of the injured vessel. Platelets also stick to each other and a viscous mass is formed. This platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness. This reinforcement is initiated by the local stimulation of the coagulation process by the expose collagen of the cut vessel and the released contents and membranes of platelets. The two pathways of blood coagulation are shown in the figure below. The circled clotting factors are dependent on vitamin K for their activation.Thrombogenesis is an altered state of hemostasis. An intravascular thrombus results from a pathological disturbance of hemostasis. The arterial thrombus is initiated by the adhesion and the release of circulating platelets to a vessel wall. This initial adhesion and the release of adenosine diphosphate (ADP) from platelets is followed by platelet-platelet aggregation. The thrombus grows to occlusive proportions in the areas of slower arterial blood flow. A platelet plug formed solely by platelet interaction is unstable. After the initial aggregation and viscous metamorphosis of platelets, fibrin becomes an important constituent of a thrombus. Production of thrombin occurs by activation of the reactions of blood coagulation at the site of the platelet mass. This thrombin stimulates further platelet aggregation not only by inducting the release of mote ADP from the platelets but also by stimulating the synthesis of prostaglandins, which are more powerful than ADP.The first orally active anticoagulant, dicoumerol, which is a molecule consisting of two 4-hydroxycoumarin moieties bonded at their 3-position via a CH2 bridge, was isolated from decomposed yellow sweet clover. It was discovered and identified because of hemorrhagic death of cattle ingesting this improperly stored feed in the early 1920s (sweet clover disease). This followed demonstration that oral use of this compound increased clotting time and decreased the incidence of post surgical intravascular thrombus formation.The oral anticoagulants are antagonists of vitamin K. Their administration to man or other animals leads to the appearance of precursors of the four vitamin K-dependent clotting factors in plasma and liver. These precursor proteins are biologically inactive in tests of coagulation. The precursor protein to prothrombin can be activated to thrombin nonphysiologically by snake venoms, demonstrating that the portion of the molecule necessary for this activity is intact. However, the prothrombin and other precursor proteins cannot bind divalent cations such as calcium and thus cannot interact with phospholipid-containing membranes, which are their normal sites of activation. This was puzzling for some time because abnormal prothrombin has the same number to amino acid residues and gives the same amino acid analysis after acid hydrolysis as does normal prothrombin. NMR studies revealed that normal prothrombin contains g-carboxyglutamate (see figure below), a previously unknown residue. The vitamin K-sensitive step in the synthesis of clotting factors is the carboxylation of ten or more glutamic acid residues at the amino-terminal end of the precursor protein to form g-carboxyglutamate. These amino acid residues are much stronger chelators of calcium than glutamate. The binding of Ca2+ by prothrombin anchors it to phospholipid membranes derived from blood platelets following injury. Th functional significance of the binding of prothrombin to phospholipid surfaces is that it brings prothrombin into close proximity with two proteins that mediate its conversion into thrombin-Factor Xa and Factor V. The amino-terminal fragment of prothrombin, which contains the Ca2+-binding sites, is released in this activation step. Thrombin free in this way from the phospholid surface can then activate fibrinogen in the plasma.In hepatic microsomes, the reduction of vitamin K to its hydroquinone form (vitamin KH2) precedes the bicarbonate-dependent carboxylation of precursor prothrombin, descarboxyprothrombin, to prothrombin (see figure below). This carboxylase activity for the synthesis of prothrombin is linked to an epoxidase activity for vitamin KH2, which oxidizes the vitamin to vitamin K epoxide (KO). An epoxide reductase, which requires NADH, converts vitamin K epoxide back to vitamin KH2. This reaction is the site of action of the coumarins and the site of genetic resistance to the coumarins, which is also characterized by an increase requirement for vitamin K. Thus it is the recycling of the vitamin to its reduced active cofactor that results ultimately in decreased thrombin levels. The vitamin K analog chloro-K1 (in which the 2-methyl group of vitamin K1 is replaced by a chloro group) directly inhibits the carboxylase and epoxidase reaction, which are not sensitive to coumarins.Vitamin K is reduced to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to protein carboxylation, wherein descarboxyprothrombin is converted to prothrombin by carboxylation of glutamate residues to g-carboxyglutamate. Enzymatic reduction of the epoxide with NADH as a cofactor regenerates vitamin KH2. The oxidation of vitamin KH2. The oxidation of vitamin K is inhibited by the chloro analog of vitamin K epoxide is the coumarin-sensitive step. Dicoumerol, the prototype of coumarin drugs, is of relatively low potency, with a slow onset of up to 5 days for peak activity and hypoprothrombinemia. The anticoagulant effect may persist for more than 1 week after stopping the drug. Even though over doses can be antidoted with vitamin K1, clinical adjustment of anticoagulation, particularly downward, is difficult. Warfarin has become the most widely used of the coumarin drugs. It is the most potent, with many patient being maintained on only 5 mg/dayWarfarin was initially introduced as a rodenticide because it was thought too dangerous for human use. It is still used in pest control. The drug, as sweetened pellets, causes rats to die from internal bleeding. In the early 1960s rats resistant to warfarin were noted in London. They were nicknamed "super rats." Several years later this phenomenon appeared in humans. It has been shown to be an inherited autosomal dominant trait. Person with this trait require a 20-fold increase in the drug to achieve anticoagulation-easily fatal to normal patients. Explanations for this unusual phenomenon have been proposed. One is that a tissue protein regulating the synthesis of one or more of the clotting factors became genetically altered. Another is a mutation in the enzyme daphorase that makes it less susceptible to coumarin drug inhibition.Edward B. Walker (Weber State University)Cardiovascular Drugs is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Case Studies: Proteins

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Proteins/Case_Studies%3A_Proteins

Angiotnesin PeptideEnkephalinesMembrane TransportMembrane transport is essential for cellular life. As cells proceed through their life cycle, a vast amount of exchange is necessary to maintain function. Transport may involve the incorporation of biological molecules and the discharge of waste products that are necessary for normal function. 1 Membrane transport refers to the movement of particles (solute) across or through a membranous barrier. 2 These membranous barriers, in the case of the cell for example, consist of a phospholipid bilayer. The phospholipids orient themselves in such a way so that the hydrophilic (polar) heads are nearest the extracellular and intracellular mediums, and the hydrophobic (non-polar) tails align between the two hydrophilic head groups. Membrane transport is dependent upon the permeability of the membrane, transmembrane solute concentration, and the size and charge of the solute. 2 Solute particles can traverse the membrane via three mechanisms: passive, facilitated, and active transport. 1 Some of these transport mechanisms require the input of energy and use of a transmembrane protein, whereas other mechanisms do not incorporate secondary molecules. 3Permanent Hair WaveThe formation of disulfide bonds has a direct application in producing curls in hair by the permanent wave process. Hair keratin consists of many protein alpha-helices. Three alpha-helices are interwoven into a left-handed coil called a protofibril. Eleven protofibrils are bonded and coiled together to make a microfibril. Hundreds of these microfibrils are cemented into an irregular bundle called a macrofibril. These in turn are mixed with dead and living cells to make a complete strand of hair.Sickle Cell AnemiaThe incorrect amino acid sequence in a protein may lead to fatal consequences. For example, the inherited disease, sickle cell anemia, results from a single incorrect amino acid at the 6th position of the beta - protein chain out of 146. Hemoglobin consists of four protein chains - two beta and two alpha. Case Studies: Proteins is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Chemistry of Vision

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Photoreceptors/Chemistry_of_Vision

Vision is such an everyday occurrence that we seldom stop to think and wonder how we are able to see the objects that surround us. Yet the vision process is a fascinating example of how light can produce molecular changes. The retina contain the molecules that undergo a chemical change upon absorbing light, but it is the brain that actually makes sense of the visual information to create an image.Light is one of the most important resources for civilization, it provides energy as it pass along by the sun. Light influence our everyday live. Living organisms sense light from the environment by photoreceptors. Light, as waves carry energy, contains energy by different wavelength. In vision, light is the stimulus input. Light energy goes into eyes stimulate photoreceptor in eyes. However, as an energy wave, energy is passed on through light at different wavelength.Light, as waves carry energy, contains energy by different wavelength. From long wavelength to short wavelength, energy increase. 400 nm to 700 nm is visible spectrum. Light energy can convert chemical to other forms. Vitamin A, also known as retinol, anti-dry eye vitamins, is a required nutrition for human health. The predecessor of vitamin A is present in the variety of plant carotene. Vitamin A is critical for vision because it is needed by the retina of eye. Retinol can be convert to retinal, and retinal is a chemical necessary for rhodopsin. As light enters the eye, the 11-cis-retinal is isomerized to the all-"trans" form.The molecule cis-retinal can absorb light at a specific wavelength. When visible light hits the cis-retinal, the cis-retinal undergoes an isomerization, or change in molecular arrangement, to all-trans-retinal. The new form of trans-retinal does not fit as well into the protein, and so a series of geometry changes in the protein begins. The resulting complex is referred to a bathrhodopsin (there are other intermediates in this process, but we'll ignore them for now).The reaction above shows Lysine side-chain from the opsin react with 11-cis-retinal when stimulated. By removing the oxygen atom form the retinal and two hydrogen atom form the free amino group of the lysine, the linkage show on the picture above is formed, and it is called Schiff base.As the protein changes its geometry, it initiates a cascade of biochemical reactions that results in changes in charge so that a large potential difference builds up across the plasma membrane. This potential difference is passed along to an adjoining nerve cell as an electrical impulse. The nerve cell carries this impulse to the brain, where the visual information is interpreted.The light image is mapped on the surface of the retina by activating a series of light-sensitive cells known as rods and cones or photoreceptors. The rods and cones convert the light into electrical impulses which are transmitted to the brain via nerve fibers. The brain then determines, which nerve fibers carried the electrical impulse activate by light at certain photoreceptors, and then creates an image.The retina is lined with many millions of photoreceptor cells that consist of two types: 7 million cones provide color information and sharpness of images, and 120 million rods are extremely sensitive detectors of white light to provide night vision. The tops of the rods and cones contain a region filled with membrane-bound discs, which contain the molecule cis-retinal bound to a protein called opsin. The resulting complex is called rhodopsin or "visual purple".In human eyes, rod and cones react to light stimulation, and a series of chemical reactions happen in cells. These cells receive light, and pass on signals to other receiver cells. This chain of process is class signal transduction pathway. Signal transduction pathway is a mechanism that describe the ways cells react and response to stimulation.Chemistry of Vision is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Cholinergic Drugs I - Nicotinic and Muscarinic Receptors

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Medicinal_Chemistry/Cholinergic_Drugs_I_-_Nicotinic_and_Muscarinic_Receptors

Neurotransmitters released from nerve terminals bind to specific receptors, which are specialized macromolecules embedded in the cell membrane. The binding action initiates a series of specific biochemical reactions in the target cell that produce a physiological response. These effects can be modified by various drugs that act as agonists or antagonists.The autonomic system consists of two major divisions: the Sympathetic Nervous System and the Parasympathetic Nervous System. These often function in antagonistic ways. A signal is transmitted from the spinal cord to peripheral areas through two successive neurons. The first neuron (preganglionic), which originates in the spinal cord, will synapse with the second neuron (postganglionic) in a ganglion. Parasympathetic ganglia tend to lie close to or within the organs or tissues that their neurons innervate, whereas sympathetic ganglia lie at a more distant site from their target organs. Both systems have associated sensory fibers that send feedback information into the central nervous system regarding the functional condition of target tissues.The significant difference between the two systems is that their postganglionic fibers secrete different neurotransmitters. Those of the parasympathetic system secrete acetylcholine (ACh), hence the name cholinergic, whereas the postganglionic fibers secrete norepinephrine (NE), hence the name adrenergic. The preganglionic fibers of both systems secrete ACh; therefore, both preganglionic fibers are cholinergic. Motor neurons which are not part of the autonomic nervous system also release acetylcholine (see .(a) Preganglionic neurons (solid line) of the sympathitic division of the autonomic nervous system release acetycholine at their synapses with postganglionic neurons (dashed line). Although exceptions occur, the postganglionic neurons release mainly norepinephrine at their function with effectors. (b) Pregangionic neurons (solid line) of the parasympathetic division of the autonomic nervous system release acetycholine at their synapses with postganglionic neurons (dashed line), and the postgangionic neurons also release acetycholine at their effectors. (c) Somatic efferent neurons release acetylcholine at their junctions with skeletal muscles.S.K.AndersonAcetylcholine acts on more than one type of receptor. Henry Dale, a British physiologist working in London in 1914, found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine. It was found that Nicotine stimulates receptors on skeletal muscle and sympathetic and parasympathetic postganglionic neurons, however, muscarine stimulates receptor sites located only at the junction between postganglionic parasympathetic neurons and the target organ. Dale therefore classified the many actions of acetylcholine into nicotinic effects and muscarinic effects. It has subsequently become clear that there are two distinct types of acetylcholine receptors affected by either muscarine or nicotine. To restate this again, nicotinic receptors cause sympathetic postganglionic neurons and parasympathetic postganglionic neurons to fire and release their chemicals and skeletal muscle to contract. Muscarinic receptors are associated mainly with parasympathetic functions and stimulates receptors located in peripheral tissues (e.g., glands, smooth muscle). Acetylcholine activates all of these sites.Advanced biochemical techniques have now shown a more fundamental difference in the two types of cholinergic receptors. The nicotinic receptor is a channel protein that, upon binding by acetylcholine, opens to allow diffusion of cations. The muscarinic receptor, on the other hand, is a membrane protein; upon stimulation by neurotransmitter, it causes the opening of ion channels indirectly, through a second messenger. For this reason, the action of a muscarinic synapse is relatively slow. Muscarinic receptors predominate at higher levels of the central nervous system, while nicotinic receptors, which are much faster acting, are more prevalent at neurons of the spinal cord and at neuromuscular junctions in skeletal muscle.A cholinergic drug is any of various drugs that inhibit, enhance, or mimic the action of the neurotransmitter acetylcholine within the body. Acetylcholine stimulation of the parasympathetic nervous system helps contract smooth muscles, dilate blood vessels, increase secretions, and slow the heart rate. Some cholinergic drugs, such as muscarine, pilocarpine, and arecoline, mimic the activity of acetylcholine in stimulating the parasympathetic nervous system. These drugs, however, have few therapeutic uses. Other cholinergic drugs, such as atropine and scopolamine, inhibit the action of acetylcholine and thus suppress all the actions of the parasympathetic nervous system. These drugs help dry up such bodily secretions as saliva and mucus and relax smooth-muscle walls. They are used therapeutically to relieve spasms of the smooth-muscle walls of the intestines, to relieve bronchial spasms, to diminish salivation and bronchial secretions during anesthesia, and to dilate the pupil during ophthalmological procedures. Nicotine is an organic compound that is the principal alkaloid of tobacco. Nicotine occurs throughout the tobacco plant and especially in the leaves. The compound constitutes about 5 percent of the plant by weight. Both the tobacco plant (Nicotiana tabacum) and the compound are named for Jean Nicot, a French ambassador to Portugal, who sent tobacco seeds to Paris in 1550.Crude nicotine was known by 1571, and the compound was obtained in purified form in 1828; the correct molecular formula was established in 1843, and the first laboratory synthesis was reported in 1904. Nicotine is one of the few liquid alkaloids. In its pure state it is a colorless, volatile base (pKa -8.5) with an oily consistency, but when exposed to light or air, it acquires a brown color and gives off a strong odor of tobacco. The complex and often unpredictable changes that occur in the body after administration of nicotine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid has both stimulant and depressant phases of action. The ultimate response of any one system represents the summation of the several different and opposing effects of nicotine. For example, the drug can increase the heart rate by excitation of sympathetic cardiac ganglia, and it can slow down the heart rate by stimulation of parasympathetic cardiac ganglia. In addition, the effects of the drug on the chemoreceptors of the carotid and aortic bodies and on medullary centers influence heart rate, as do also the cardiovascular compensatory reflexes resulting from changes in blood pressure caused by nicotine. Finally, nicotine causes a discharge of epinephrine from the adrenal medulla, and this hormone accelerates cardiac rate and raises blood pressure.Nicotine is unique in its biphasic effects. In the medulla, small doses of nicotine evoke the discharge of catacholamines, and in larger doses prevent their release in response to splanic nerve stimulation. Its biphasic effect causes a stimulant effect when inhaled in short puffs, but when smoked in deep drags it can have a tranquilizing effect. This is why smoking can feel invigorating at some times and can seem to block stressful stimuli at others.Nicotine markedly stimulates the central nervous system (CNS). Appropriate doses produce tremors in both man and laboratory animals; with somewhat larger dose, the tremor is followed by convulsions. The excitation of respiration is a prominent action of nicotine; although large doses act directly on the medulla oblongata, smaller doses augment respiration reflexly by excitation of the chemoreceptors of the carotid and aortic bodies. Stimulation of the CNA is followed by depression, and death usually results from failure of respiration due to both central analysis and peripheral blockade of muscles of respiration. Nicotine also causes vomiting by central and peripheral actions. The central component of the vomiting response is due to stimulation of the chemoreceptor trigger zone is in the medulla.oblongata. In addition, nicotine activates vagal and spinal afferent nerves that from the sensory input of the reflex pathways involved in the act of vomiting.Although acetylcholine causes vasodilation and a decrease in heart rate, when administered intravenously to the dog, nicotine characteristically produces an increase in heart rate and blood pressure. This is because in general, the cardiovascular responses to nicotine are due to stimulation of the sympathetic ganglia and the adrenal medulla, together with the discharge of catacholamines from sympathetic nerve endings.Nicotine is commercially obtained from tobacco scraps and is used as an insecticide and as a veterinary vermifuge (wormer). Nitric acid or other oxidizing agents convert nicotine to nicotinic acid, or niacin, which is used as a food supplement.Medicinal UsesTabaccoNicotine AddictionMiscellaneousMuscarine, and alkaloid obtained from the poisonous mushroom Amanita Muscaria, produces the effects predictable from stimulation of postgangiolinc parasympathetic fibers. The symptoms usually occur within 15-30 minutes of ingestion or injection, and are focused on the involuntary nervous system. The muscarinic alkaloids stimulate the smooth muscle and therby increase motility; large doses cause spasm and severe diarrhea. The bronchial musculature is also stimulated, causing asmatic-like attacks. Excessive salivation, sweating, tears, lactation (in pregnant women), plus severe vomiting also occur. The most prominent cardiovascular effects are the a marked fall in the blood pressure and a slowing or temporarily cessation of the heart. Victims normally recover within 24 hours, but severe cases may result in death due to respiratory failure. All effects of muscarine-like drugs are prevented by the alkaloid atropine. Furthermore, neither atropine-like nor muscarine-like drugs show effects at the neuromuscular junction.Although muscarine and muscarine like alkaloids are of great value as pharmacological tools, present clinical use is largely restricted. Since evidence is beginning to accumulate that there are distinct subtypes of muscarinic receptors, there has been a renewed interest in synthetic analogs that may enhance the tissue selectivity of muscarinic agonists.Edward B. Walker (Weber State University)Cholinergic Drugs I - Nicotinic and Muscarinic Receptors is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Cis-Trans Isomerization of Retinal

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Photoreceptors/Chemistry_of_Vision/Cis-Trans_Isomerization_of_Retinal

Conversion of Vitamin A into Cis-RetinalIsomerization of RetinalContributorsVitamin A, trans-retinol, is carried to the rods in the eyes from storage in the liver. First it is converted to cis-retinol by a process of isomerization, which means that the trans isomer is converted to a cis isomer. The molecule must break the pi bond, rotate on the single bond, and reform the pi bond. The cis-retinol, an alcohol, is then oxidized to cis-retinal, an aldehyde.Photochemical events in vision involve the protein opsin and the cis/trans isomers of retinal. The cis-retinal fits into a receptor site of opsin. Upon absorption of a photon of light in the visible range, cis-retinal can isomerize to all-trans-retinal. In the cis-retinal, the hydrogens (light gray in the molecular model on the left) are on the same side of the double bond (yellow in the molecular model).In the trans-retinal, the hydrogens are on opposite sides of the double bond. In fact, all of the double bonds are in the trans-configuration in this isomer: the hydrogens, or hydrogen and -CH3, are always on opposite sides of the double bonds (hence, the name "all-trans-retinal").Note how the shape of the molecule changes as a result of this isomerization. The molecule changes from an overall bent structure to one that is more or less linear. All of this is the result of trigonal planar bonding (120 o bond angles) about the double bonds.This photochemical reaction is best understood in terms of molecular orbitals, orbital energy, and electron excitation. In cis-retinal, absorption of a photon promotes a p electron in the pi bond to a higher-energy orbital. This excitation "breaks" the pi component of the double bond and is temporarily converted into a single bond. This means the molecule can now rotate around this single bond, which it does by swiveling through 180o.The double bond then reforms and locks the molecule back into position in a trans configuration of the all-trans-retinal. This isomerization occurs in a few picoseconds (10-12 s) or less. Energy from light is crucial for this isomerization process: absorption of a photon leads to breaking the double bond and consequent isomerization about half the time (in the dark is almost never happens.Cis-Trans Isomerization of Retinal is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

Cobalamin 1

https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Vitamins_Cofactors_and_Coenzymes/Vitamin_B%3A_Cobalamin/Cobalamin_1

Cobalamin or Vitamin B12, a water soluble vitamin that has known functions for improving brain and nerve cells, and the production of adequate blood cells.1 It is commonly found in meats, poultry, dairy products, eggs and seafood. However, organisms such as bacteria and algae are also known to produce the active form of vitamin B12 through fermentation. The structure of cobalamin is unique with the central atom; cobalt, that has potential for metalloenzyme active sites. In particular, coenzyme B12 or adenosylcobalamin (AdoCbl) is an essential for several enzymes such as methylmaonly-CoA mutase, diol dehydratase, and ethanolamine ammonia lyase.2 Cobalamin is an important biologically active, though small, enzyme involved in several configurational changes on its active site. As the name suggests, Cobalamin incorporates several structural elements surrounding a cobalt atom as the metalloenzyme active site. The vitamin-B12 configuration of Cobalamin that is of importance to biological life, primarily in the function of mechanisms in the liver, is that of Cyanocobalamin, one of the rare cases where a cyanide group is presently ingested by living organisms where otherwise would be toxic. Four main forms of Cobalamin exist and are interchanged in the body as the B12 performs various functions. The Cyanocobalamin used as the B12 vitamin supplement however is not naturally occurring, and must be generated then ingested in order to configurationally lose its cyanide group for a methyl group. Various functions in cell metabolism are involved with the transfer of the removable ligand group on the Cobalamin active site, most importantly is the transfer of methyl groups thus acting as a catalyst between configurational changes in many enzymes.AdenosylcobalaminCobalamin has a formula C63H88CoN14o14P and molecular mass 1355.37 g/mol. This is a fairly large molecule, thus, analyzing the structure confirmation can determine the point group. The structure contains sigma vertical planes and has no sigma horizontal plane. The central atom, Cobalt, has an R attached that makes the molecule unique in several enzymatic catalyses. The point group of Cobalamin is assigned as C4v.Minimal mechanism of diol dehydratase reaction. The mechanism of diol dehydrates is known to catalyzes the conversion of 1,2-diols to the corresponding aldehydes. shows a mechanism for this enzymatic dehydration that involves the hydrogen atom abstraction from C1 (1,2-diol) and the migration of an OH group from C2 to C1 of 1,2-propanediol. The adenosyl (AdoCH2) radical that is generated by the hemolytic cleavage of the Co-C covalent bond in AdoCbl plays an essential role in this OH group migration and thus effectively promotes this chemically difficult reaction.2 Therefore, the OH group on C2 migrates to C1 leading to a formation of a 1,1-diol radical, which leads to the formation of the 1-1-diol and the regeneration of AdoCH2 radical. The crystal structure of diol dehydratase with cyanocobalamin and adeninlypentylcobalamin have shown that both the OH groups of substrate coordinate directly to K+ ion at the active site, which implies the participation of K+ ion in the OH group migration.3 Kamachi and colleagues performed density functional theory to reveal the catalytic roles of K+ ion in the diol dehydratase reaction. As a result, the course of a reaction the substrate and the radical intermediates are always bound to K+ ion until the release of product aldehyde from the active site and that OH group proceed with the aid of K+. Therefore, the role of K+ ion have suggest that it is the most important role in the reaction to fix the substrate and the intermediates in a proper position in order to ensure the hydrogen abstraction and recombination. shows the optimized structure of the enzyme in the QM region. K+ ion is corresponding to the five oxygen atoms originated from the side chain of Gln141, Glu170, Glu221, Gln296, and the carbonyl group of Ser352.2 The sixth and the seventh coordination positions are occupied by O1 and O2 of the substrates (S)-1,2-propanediol (PDO); the S-enantiomer is preferred in the binding by enzyme.2 The ribose moiety of 5’-deoxyadenosyl radical and the side chain of His143 are also involved in the QM region. The interaction of the migrating OH group with the imidazolum ion of His143 has been considered to be essential for the stabilization of the transition state for the OH migration. The Ribosyl rotation for the radical transfer from AdoCbl to substrate can essentially promote the Co-C cleavage upon binding to apodiol dehydratase, where adeninylpropylcobalamin (AdePeCbl) and other longer chain homologues cannot.2 The presence of the adenine-binding site in dio dehydratase was recently determined by the crystal structure analysis of the diol hydratase-AdePeCbl complex.8 The crystal structure shows that the adenine moiety of this analogue is trapped by hydrogen-bonding network with a water molecule and surrounding amion acid residues, Ser224, Ser229, Ser301, and Gly261.2 For this reason, the adenine-binding pocket fixes the adenine ring to allow tight binding of adenylpentyl group to the Co atom at a distance of 1.89 A, which is the main reason for the catalytic inactivity of the analogue. [NEED TO RELOAD THIS IMAGE PROPERLY]Active site structure of diol dehydratase.Figure 4, part A shows an X-ray structure of the diol dehydratase-AdePeCbl complex. Part B shows Diol dehydratase-AdoCbl model complex produced by replacing the pentyl moiety of A with ribose. Part C shows the optimized structure of the diol dehydratase- AdoCbl complex model after the rotation of the ribose moiety.4 However, there is still argument whether the K+ ion in the active site remains with the substrate and radical intermediates through the reaction. Further studies could contribute to the understanding of hydrogen bonds to the active site residues, hydrogen abstraction and the steroselective hydrogen recombination. Where R = -OH, Hydroxycobalamin, -CN, Cyanocobalamin, -Me, Methylcobalamin, -Ado, 5-deoxyadensosine. The Cyanocobalamin is generated in-situ by bacteria in the gastrointestinal systems of many mammals, or by the carbonization of Hydroxycobalamin created by other types of bacteria when exposed to a charcoal environment. While the B12 ingested may be the Cyanocobalamin, the cyanide group is removed in the body when absorbed and is decomposed in the process of removal. Once in the body, the B12 structure is used in the transport of methyl groups in DNA construction as well as 5-deoxyadensosine in mitochondrial energy production in cells. However important this B12 interaction is in the human body, humans don't naturally utilize nor produce any of this B12, rather the functional use of Folic Acid in the body is merely replaced by Cobalamin. As a result, many health effects of both deficiency of B12 or folic acid can be rectified by the addition of the other if need be. Deficiency of either B12 or folic acid can result in several neurological disorders and lack of motivation or onset of depression, which can possibly be related to the available energy production in cells being altered or slowed down due to this deficiency. However, too much Cobalamin in the human blood stream can potentially lead to several serious diseases, many effects of which are still being researched and less understood due to its homogenous behavior alongside other compounds already present in the human body, such as folic acid. Several of these diseases are both the cause of overutilization of Cobalamin, and the resulting effect of which, including several types of leukemia, resulting in the high levels of Cobalamin being stored in tissues. This large amount of stored Cobalamin being involved in the high presence of haptocorrin, from the corrin portion of the cobalamin structure, leading to several, some life threatening, liver diseases. Even though The active site of the cobalt metal in Cobalamin possesses an octahedral configuration, forming primary sigma bonds with the transfer ligand, R, and the amine ring in the Corrin ring structure, while secondary pi-type bonding occurs in the three planar imidazole-type rings of the Corrin structure, and with the imidazole-type rings below axis, as shown above. This structural configuration allows a unique electron configuration along with nearby pi-system stabilization making the cobalt atom active site a preferred and semi-stable target for transferring the hydroxyl, methyl, cyano, and 5-deoxyadensosine in the various functions of its enzyme catalysis action. If only the three planar and one sub-axial ligand bonds from the nitrogens in the imidazole-like ring structures are taken as identical, and the sigma bonding amine group and 'R' active site group are taken as separate, the cobalt and its immediate ligand environment can be seen to possibly possess a Cs type symmetry with one mirror plane running through the R and amine ligands. Though the above Cs symmetry applies if only the simple immediate ligand environment is considered, because of the complexity in the structure of the actual surrounding Corrin ring and Nucleotide loop in the plane and below the active site of the imidazole-type structures can't in reality be taken as identical once the structure is extended beyond a couple bond lengths away. Though this may be the case, the immediate electron density of the supposed identical imidazole-type ring groups connected to the cobalt metal may be considered near identical enough to promote the rotational configuration of the 'R' group attached to be related to the amine ligand link instead. For the R groups being -OH, -CN, or Me this has no effect whatsoever on the bonding rotation as these ligands are considered symmetric along the attachment site, however the 5-deoxyadensosine link used extensively in the energy production in cells will be effected by this symmetry of the active site, and could potentially be one reason this Cobalamin performs well in the transfer of these groups. Cobalamin is an important compound used in the human body which is used in various configurations for specific tasks in enzymatic catalysis in subgroup transfer between systems, though not naturally utilized, it is more of a replacement for Folic Acid in the human body for these same functions, making it an important vitamin in sufficient, but not over extensive, quantities. Cobalamin 1 is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.