Citric acid cycle - wikipedia Citric acid cycle Overview of the citric acid cycle The citric acid cycle ( CAC ) -- also known as the tricarboxylic acid ( TCA ) cycle or the Krebs cycle -- is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl - CoA derived from carbohydrates, fats, and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate ( ATP ). In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically. The name of this metabolic pathway is derived from the citric acid ( a type of tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH ) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate ( in the form of acetyl - CoA ) and water, reduces NAD to NADH, and produces carbon dioxide as a waste byproduct. The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation ( electron transport ) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. In prokaryotic cells, such as bacteria which lack mitochondria, the citric acid cycle reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the cell 's surface ( plasma membrane ) rather than the inner membrane of the mitochondrion Contents 1 Discovery 2 Evolution 3 Overview 4 Steps 5 Structure of intermediates in Fischer projections and polygonal model 6 Products 7 Efficiency 8 Variation 9 Regulation 10 Major metabolic pathways converging on the citric acid cycle 11 Citric acid cycle intermediates serve as substrates for biosynthetic processes 12 Interactive pathway map 13 Glucose feeds the TCA cycle via circulating Lactate 14 See also 15 References 16 External links Discovery Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of Albert Szent - Györgyi, who received the Nobel Prize in Physiology or Medicine in 1937 specifically for his discoveries pertaining to fumaric acid, a key component of the cycle. The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebs and William Arthur Johnson while at the University of Sheffield, for which the former received the Nobel Prize for Physiology or Medicine in 1953, and for whom the cycle is sometimes named ( Krebs cycle ). Evolution Components of the citric acid cycle were derived from anaerobic bacteria, and the TCA cycle itself may have evolved more than once. Theoretically, several alternatives to the TCA cycle exist ; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle. Overview Structural diagram of acetyl - CoA : The portion in blue, on the left, is the acetyl group ; the portion in black is coenzyme A. The citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize acetate, in the form of acetyl - CoA, into two molecules each of carbon dioxide and water. Through catabolism of sugars, fats, and proteins, the two - carbon organic product acetyl - CoA ( a form of acetate ) is produced which enters the citric acid cycle. The reactions of the cycle also convert three equivalents of nicotinamide adenine dinucleotide ( NAD ) into three equivalents of reduced NAD ( NADH ), one equivalent of flavin adenine dinucleotide ( FAD ) into one equivalent of FADH, and one equivalent each of guanosine diphosphate ( GDP ) and inorganic phosphate ( P ) into one equivalent of guanosine triphosphate ( GTP ). The NADH and FADH generated by the citric acid cycle are, in turn, used by the oxidative phosphorylation pathway to generate energy - rich ATP. One of the primary sources of acetyl - CoA is from the breakdown of sugars by glycolysis which yield pyruvate that in turn is decarboxylated by the enzyme pyruvate dehydrogenase generating acetyl - CoA according to the following reaction scheme : CH C ( = O ) C ( = O ) O pyruvate + HSCoA + NAD → CH C ( = O ) SCoA acetyl - CoA + NADH + CO The product of this reaction, acetyl - CoA, is the starting point for the citric acid cycle. Acetyl - CoA may also be obtained from the oxidation of fatty acids. Below is a schematic outline of the cycle : The citric acid cycle begins with the transfer of a two - carbon acetyl group from acetyl - CoA to the four - carbon acceptor compound ( oxaloacetate ) to form a six - carbon compound ( citrate ). The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO. The carbons lost as CO originate from what was oxaloacetate, not directly from acetyl - CoA. The carbons donated by acetyl - CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl - CoA - donated carbons as CO requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they might not be lost, since many citric acid cycle intermediates are also used as precursors for the biosynthesis of other molecules. Most of the energy made available by the oxidative steps of the cycle is transferred as energy - rich electrons to NAD, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced. Electrons are also transferred to the electron acceptor Q, forming QH ( Q = FAD+, QH = FADH ). For every NADH and FADH that are produced in the citric acid cycle, 2.5 and 1.5 ATP molecules are generated in oxidative phosphorylation, respectively. At the end of each cycle, the four - carbon oxaloacetate has been regenerated, and the cycle continues. Steps Two carbon atoms are oxidized to CO, the energy from these reactions is transferred to other metabolic processes through GTP ( or ATP ), and as electrons in NADH and QH. The NADH generated in the citric acid cycle may later be oxidized ( donate its electrons ) to drive ATP synthesis in a type of process called oxidative phosphorylation. FADH is covalently attached to succinate dehydrogenase, an enzyme which functions both in the CAC and the mitochondrial electron transport chain in oxidative phosphorylation. FADH, therefore, facilitates transfer of electrons to coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the succinate : ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain. The citric acid cycle is continuously supplied with new carbon in the form of acetyl - CoA, entering at step 0 below. Substrates Products Enzyme Reaction type 0 / 10 Oxaloacetate + Acetyl CoA + H O Citrate + CoA - SH Citrate synthase Aldol condensation irreversible, extends the 4C oxaloacetate to a 6C molecule Citrate cis - Aconitate + H O Aconitase Dehydration reversible isomerisation cis - Aconitate + H O Isocitrate Hydration Isocitrate + NAD Oxalosuccinate + NADH + H Isocitrate dehydrogenase Oxidation generates NADH ( equivalent of 2.5 ATP ) Oxalosuccinate α - Ketoglutarate + CO Decarboxylation rate - limiting, irreversible stage, generates a 5C molecule 5 α - Ketoglutarate + NAD + CoA - SH Succinyl - CoA + NADH + H + CO α - Ketoglutarate dehydrogenase Oxidative decarboxylation irreversible stage, generates NADH ( equivalent of 2.5 ATP ), regenerates the 4C chain ( CoA excluded ) 6 Succinyl - CoA + GDP + P Succinate + CoA - SH + GTP Succinyl - CoA synthetase substrate - level phosphorylation or ADP → ATP instead of GDP → GTP, generates 1 ATP or equivalent Condensation reaction of GDP + P and hydrolysis of Succinyl - CoA involve the H O needed for balanced equation. 7 Succinate + ubiquinone ( Q ) Fumarate + ubiquinol ( QH ) Succinate dehydrogenase Oxidation uses FAD as a prosthetic group ( FAD → FADH in the first step of the reaction ) in the enzyme, generates the equivalent of 1.5 ATP 8 Fumarate + H O L - Malate Fumarase Hydration Hydration of C-C double bond 9 L - Malate + NAD Oxaloacetate + NADH + H Malate dehydrogenase Oxidation reversible ( in fact, equilibrium favors malate ), generates NADH ( equivalent of 2.5 ATP ) 10 / 0 Oxaloacetate + Acetyl CoA + H O Citrate + CoA - SH Citrate synthase Aldol condensation This is the same as step 0 and restarts the cycle. The reaction is irreversible and extends the 4C oxaloacetate to a 6C molecule Mitochondria in animals, including humans, possess two succinyl - CoA synthetases : one that produces GTP from GDP, and another that produces ATP from ADP. Plants have the type that produces ATP ( ADP - forming succinyl - CoA synthetase ). Several of the enzymes in the cycle may be loosely associated in a multienzyme protein complex within the mitochondrial matrix. The GTP that is formed by GDP - forming succinyl - CoA synthetase may be utilized by nucleoside - diphosphate kinase to form ATP ( the catalyzed reaction is GTP + ADP → GDP + ATP ). Structure of intermediates in Fischer projections and polygonal model The intermediates of citric cycle depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation. Structure of intermediates of citric acid cycle showed using Fischer projections, left, and polygonal model, right. Two - carbon molecule acetyl in the activated form acetyl - CoA ( AcoA ), on the top, condensate with four carbon molecule oxaloacetate ( OxA ) to form citrate ( Cit ). The next intermediates are, respectively, cis - aconitate ( CisA ), isocitrate ( IsoC ), oxalosuccinate ( OxS ), alphaketoglutarate ( AKG ), succinyl - CoA ( ScoA ), succinate ( Suc ), fumarate ( Fum ), malate ( Mal ), so the oxaloacetate is regenerated. The process can be followed in more detail, with the two carbons of the acetyl group of acetyl - CoA showed in blue is incorporated from citrate to succinyl - CoA in specific part of the species, and after this step the carbon is no further distinguishable since succinate is a symmetric molecule. The enzymes involved in this pathway correspond to citrate synthase ( ( 1 ), aconitase ( ( 2 ), isocitrate dehydrogenase ( 3 ), alphaketoglutarate dehydrogenase ( 4 ), succinyl - CoA synthetase ( 5 ), succinate dehydrogenase ( 6 ), fumarase ( 7 ), and malate dehydrogenase ( 8 ). Coenzymes ( CoA - SH, NAD, NADH + H, FAD, FADH, ATP or GTP and ADP or GDP ), CO and H O were omitted in these representations. The productions of NADH and FADH from the oxidized forms of coenzymes are represented, respectively, as the release of `` 2H '' and `` ( 2H ) ''. The production of ATP or GTP from ADP or GDP is shown by the release of high energy phosphate `` ~ P ''. Products Products of the first turn of the cycle are one GTP ( or ATP ), three NADH, one QH, and two CO. Because two acetyl - CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are : two GTP, six NADH, two QH, and four CO. Description Reactants Products The sum of all reactions in the citric acid cycle is : Acetyl - CoA + 3 NAD + Q + GDP + P + 2 H O → CoA - SH + 3 NADH + 3 H + QH + GTP + 2 CO Combining the reactions occurring during the pyruvate oxidation with those occurring during the citric acid cycle, the following overall pyruvate oxidation reaction is obtained : Pyruvate ion + 4 NAD + Q + GDP + P + 2 H O → 4 NADH + 4 H + QH + GTP + 3 CO Combining the above reaction with the ones occurring in the course of glycolysis, the following overall glucose oxidation reaction ( excluding reactions in the respiratory chain ) is obtained : Glucose + 10 NAD + 2 Q + 2 ADP + 2 GDP + 4 P + 2 H O → 10 NADH + 10 H + 2 QH + 2 ATP + 2 GTP + 6 CO The above reactions are balanced if P represents the H PO ion, ADP and GDP the ADP and GDP ions, respectively, and ATP and GTP the ATP and GTP ions, respectively. The total number of ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 30 and 38. Efficiency The theoretical maximum yield of ATP through oxidation of one molecule of glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is 38 ( assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH ). In eukaryotes, two equivalents of NADH are generated in glycolysis, which takes place in the cytoplasm. Transport of these two equivalents into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase / proton pump commonly reduces the ATP yield from NADH and FADH to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~ 2.5 ATP per NADH and ~ 1.5 ATP per FADH, further reducing the total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton - to - ATP ratios provides an estimate of 29.85 ATP per glucose molecule. Variation While the citric acid cycle is in general highly conserved, there is significant variability in the enzymes found in different taxa ( note that the diagrams on this page are specific to the mammalian pathway variant ). Some differences exist between eukaryotes and prokaryotes. The conversion of D - threo - isocitrate to 2 - oxoglutarate is catalyzed in eukaryotes by the NAD - dependent EC 1.1. 1.41, while prokaryotes employ the NADP - dependent EC 1.1. 1.42. Similarly, the conversion of ( S ) - malate to oxaloacetate is catalyzed in eukaryotes by the NAD - dependent EC 1.1. 1.37, while most prokaryotes utilize a quinone - dependent enzyme, EC 1.1. 5.4. A step with significant variability is the conversion of succinyl - CoA to succinate. Most organisms utilize EC 6.2. 1.5, succinate -- CoA ligase ( ADP - forming ) ( despite its name, the enzyme operates in the pathway in the direction of ATP formation ). In mammals a GTP - forming enzyme, succinate -- CoA ligase ( GDP - forming ) ( EC 6.2. 1.4 ) also operates. The level of utilization of each isoform is tissue dependent. In some acetate - producing bacteria, such as Acetobacter aceti, an entirely different enzyme catalyzes this conversion -- EC 2.8. 3.18, succinyl - CoA : acetate CoA - transferase. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms. Some bacteria, such as Helicobacter pylori, employ yet another enzyme for this conversion -- succinyl - CoA : acetoacetate CoA - transferase ( EC 2.8. 3.5 ). Some variability also exists at the previous step -- the conversion of 2 - oxoglutarate to succinyl - CoA. While most organisms utilize the ubiquitous NAD - dependent 2 - oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin - dependent 2 - oxoglutarate synthase ( EC 1.2. 7.3 ). Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl - CoA entirely, and convert 2 - oxoglutarate to succinate via succinate semialdehyde, using EC 4.1. 1.71, 2 - oxoglutarate decarboxylase, and EC 1.2. 1.79, succinate - semialdehyde dehydrogenase. Regulation The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of metabolic energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, α - ketoglutarate dehydrogenase, and also citrate synthase. Acetyl - coA inhibits pyruvate dehydrogenase, while succinyl - CoA inhibits alpha - ketoglutarate dehydrogenase and citrate synthase. When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α - ketoglutarate dehydrogenase ; however, ATP levels do not change more than 10 % in vivo between rest and vigorous exercise. There is no known allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10 %. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. It activates pyruvate dehydrogenase phosphatase which in turn activates the pyruvate dehydrogenase complex. Calcium also activates isocitrate dehydrogenase and α - ketoglutarate dehydrogenase. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway. Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1, 6 - bisphosphate, a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme. Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of hypoxia - inducible factors ( HIF ). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is synthesized consititutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4 - hydroxylases. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF. Major metabolic pathways converging on the citric acid cycle Several catabolic pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions, from the Greek meaning to `` fill up ''. These increase the amount of acetyl CoA that the cycle is able to carry, increasing the mitochondrion 's capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed `` cataplerotic '' reactions. In this section and in the next, the citric acid cycle intermediates are indicated in italics to distinguish them from other substrates and end - products. Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix. Here they can be oxidized and combined with coenzyme A to form CO, acetyl - CoA, and NADH, as in the normal cycle. However, it is also possible for pyruvate to be carboxylated by pyruvate carboxylase to form oxaloacetate. This latter reaction `` fills up '' the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle 's capacity to metabolize acetyl - CoA when the tissue 's energy needs ( e.g. in muscle ) are suddenly increased by activity. In the citric acid cycle all the intermediates ( e.g. citrate, iso - citrate, alpha - ketoglutarate, succinate, fumarate, malate and oxaloacetate ) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl - CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell. Acetyl - CoA, on the other hand, derived from pyruvate oxidation, or from the beta - oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl - CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl - CoA that produces CO and water, with the energy thus released captured in the form of ATP. In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway which converts lactate and de-aminated alanine into glucose, under the influence of high levels of glucagon and / or epinephrine in the blood. Here the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate ( malate ) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis. In protein catabolism, proteins are broken down by proteases into their constituent amino acids. Their carbon skeletons ( i.e. the de-aminated amino acids ) may either enter the citric acid cycle as intermediates ( e.g. alpha - ketoglutarate derived from glutamate or glutamine ), having an anaplerotic effect on the cycle, or, in the case of leucine, isoleucine, lysine, phenylalanine, tryptophan, and tyrosine, they are converted into acetyl - CoA which can be burned to CO and water, or used to form ketone bodies, which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath. These latter amino acids are therefore termed `` ketogenic '' amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via malate which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into glucose. These are the so - called `` glucogenic '' amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as oxaloacetate ( an anaplerotic reaction ) or as acetyl - CoA to be disposed of as CO and water. In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde - 3 - phosphate by way of gluconeogenesis. In many tissues, especially heart and skeletal muscle tissue, fatty acids are broken down through a process known as beta oxidation, which results in the production of mitochondrial acetyl - CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene bridges produces propionyl - CoA, which is then converted into succinyl - CoA and fed into the citric acid cycle as an anaplerotic intermediate. The total energy gained from the complete breakdown of one ( six - carbon ) molecule of glucose by glycolysis, the formation of 2 acetyl - CoA molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent oxidation of the resulting 3 molecules of acetyl - CoA is 40. Citric acid cycle intermediates serve as substrates for biosynthetic processes In this subheading, as in the previous one, the TCA intermediates are identified by italics. Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle. Acetyl - CoA can not be transported out of the mitochondrion. To obtain cytosolic acetyl - CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by ATP citrate lyase into acetyl - CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate ( and then converted back into oxaloacetate to transfer more acetyl - CoA out of the mitochondrion ). The cytosolic acetyl - CoA is used for fatty acid synthesis and the production of cholesterol. Cholesterol can, in turn, be used to synthesize the steroid hormones, bile salts, and vitamin D. The carbon skeletons of many non-essential amino acids are made from citric acid cycle intermediates. To turn them into amino acids the alpha keto - acids formed from the citric acid cycle intermediates have to acquire their amino groups from glutamate in a transamination reaction, in which pyridoxal phosphate is a cofactor. In this reaction the glutamate is converted into alpha - ketoglutarate, which is a citric acid cycle intermediate. The intermediates that can provide the carbon skeletons for amino acid synthesis are oxaloacetate which forms aspartate and asparagine ; and alpha - ketoglutarate which forms glutamine, proline, and arginine. Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the purines that are used as the bases in DNA and RNA, as well as in ATP, AMP, GTP, NAD, FAD and CoA. The pyrimidines are partly assembled from aspartate ( derived from oxaloacetate ). The pyrimidines, thymine, cytosine and uracil, form the complementary bases to the purine bases in DNA and RNA, and are also components of CTP, UMP, UDP and UTP. The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, succinyl - CoA. These molecules are an important component of the hemoproteins, such as hemoglobin, myoglobin and various cytochromes. During gluconeogenesis mitochondrial oxaloacetate is reduced to malate which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then decarboxylated to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase, which is the rate limiting step in the conversion of nearly all the gluconeogenic precursors ( such as the glucogenic amino acids and lactate ) into glucose by the liver and kidney. Because the citric acid cycle is involved in both catabolic and anabolic processes, it is known as an amphibolic pathway. Interactive pathway map Click on genes, proteins and metabolites below to link to respective articles. 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Jump up ^ Ferre, P. ; F. Foufelle ( 2007 ). `` SREBP - 1c Transcription Factor and Lipid Homeostasis : Clinical Perspective ''. Hormone Research. 68 ( 2 ) : 72 -- 82. doi : 10.1159 / 000100426. PMID 17344645. Retrieved 2010 - 08 - 30. this process is outlined graphically in page 73 Jump up ^ TY - JOUR AU - Hui, Sheng AU - Ghergurovich, Jonathan M. AU - Morscher, Raphael J. AU - Jang, Cholsoon AU - Teng, Xin AU - Lu, Wenyun AU - Esparza, Lourdes A. AU - Reya, Tannishtha AU - Le Zhan, AU - Yanxiang Guo, Jessie AU - White, Eileen AU - Rabinowitz, Joshua D. TI - Glucose feeds the TCA cycle via circulating lactate JA - Nature PY - 2017 / 10 / 18 / online VL - advance online publication SP - EP - PB - Macmillan Publishers Limited, part of Springer Nature. All rights reserved. SN - 1476 - 4687 UR - https://dx.doi.org/10.1038/nature24057 L3 - 10.1038 / nature24057 M3 - Letter L3 - http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature24057.html#supplementary-information ER - External links An animation of the citric acid cycle at Smith College Citric acid cycle variants at MetaCyc Pathways connected to the citric acid cycle at Kyoto Encyclopedia of Genes and Genomes Introduction at Khan Academy metpath : Interactive representation of the citric acid cycle Metabolism, catabolism, anabolism General Metabolic pathway Metabolic network Primary nutritional groups Energy metabolism Aerobic respiration Glycolysis → Pyruvate decarboxylation → Citric acid cycle → Oxidative phosphorylation ( electron transport chain + ATP synthase ) Anaerobic respiration Electron acceptors are other than oxygen Fermentation Glycolysis → Substrate - level phosphorylation ABE Ethanol Lactic acid Specific paths Protein metabolism Protein synthesis Catabolism Carbohydrate metabolism ( carbohydrate catabolism and anabolism ) Human Glycolysis ⇄ Gluconeogenesis Glycogenolysis ⇄ Glycogenesis Pentose phosphate pathway Fructolysis Galactolysis Glycosylation N - linked O - linked Nonhuman Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation Xylose metabolism Radiotrophism Lipid metabolism ( lipolysis, lipogenesis ) Fatty acid metabolism Fatty acid degradation ( Beta oxidation ) Fatty acid synthesis Other Steroid metabolism Sphingolipid metabolism Eicosanoid metabolism Ketosis Reverse cholesterol transport Amino acid Amino acid synthesis Urea cycle Nucleotide metabolism Purine metabolism Nucleotide salvage Pyrimidine metabolism Other Metal metabolism Iron metabolism Ethanol metabolism Citric acid cycle metabolic pathway Acetyl - CoA + H O Oxaloacetate NADH + H NAD Malate H O Fumarate FADH FAD Succinate CoA + ATP ( GTP ) P + ADP ( GDP ) Succinyl - CoA NADH + H + CO CoA NAD Citrate H O cis - Aconitate H O Isocitrate NAD ( P ) NAD ( P ) H + H Oxalosuccinate CO 2 - oxoglutarate Metabolism map Carbon Fixation Photo - respiration Pentose Phosphate Pathway Citric Acid Cycle Glyoxylate Cycle Urea Cycle Fatty Acid Synthesis Fatty Acid Elongation Beta Oxidation Peroxisomal Beta Oxidation Glyco - genolysis Glyco - genesis Glyco - lysis Gluconeo - genesis Decarb - oxylation Fermentation Keto - lysis Keto - genesis feeders to Gluconeo - genesis Direct / C4 / CAM Carbon Intake Light Reaction Oxidative Phosphorylation Amino Acid Deamination Citrate Shuttle Lipogenesis Lipolysis Steroidogenesis MVA Pathway MEP Pathway Shikimate Pathway Transcription & Replication Translation Proteolysis Glycosy - lation Sugar Acids Double / Multiple Sugars & Glycans Simple Sugars Inositol - P Amino Sugars & Sialic Acids Nucleotide Sugars Hexose - P Triose - P Glycerol P - glycerates Pentose - P Tetrose - P Propionyl - CoA Succinate Acetyl - CoA Pentose - P P - glycerates Glyoxylate Photosystems Pyruvate Lactate Acetyl - CoA Citrate Oxalo - acetate Malate Succinyl - CoA α - Keto - glutarate Ketone Bodies Respiratory Chain Serine Group Alanine Branched - chain Amino Acids Aspartate Group Homoserine Group & Lysine Glutamate Group & Proline Arginine Creatine & Polyamines Ketogenic & Glucogenic Amino Acids Amino Acids Shikimate Aromatic Amino Acids & Histidine Ascorbate ( Vitamin C ) δ - ALA Bile Pigments Hemes Cobalamins ( Vitamin B ) Various Vitamin B 's Calciferols ( Vitamin D ) Retinoids ( Vitamin A ) Quinones ( Vitamin K ) & Carotenoids ( Vitamin E ) Cofactors Vitamins & Minerals Antioxidants PRPP Nucleotides Nucleic Acids Proteins Glycoproteins & Proteoglycans Chlorophylls MEP MVA Acetyl - CoA Polyketides Terpenoid Backbones Terpenoids & Carotenoids ( Vitamin A ) Cholesterol Bile Acids Glycero - phospholipids Glycerolipids Acyl - CoA Fatty Acids Glyco - sphingolipids Sphingolipids Waxes Polyunsaturated Fatty Acids Neurotransmitters & Thyroid Hormones Steroids Endo - cannabinoids Eicosanoids Major metabolic pathways in metro - style map. Click any text ( name of pathway or metabolites ) to link to the corresponding article. Single lines : pathways common to most lifeforms. Double lines : pathways not in humans ( occurs in e.g. plants, fungi, prokaryotes ). Orange nodes : carbohydrate metabolism. Violet nodes : photosynthesis. Red nodes : cellular respiration. Pink nodes : cell signaling. Blue nodes : amino acid metabolism. Grey nodes : vitamin and cofactor metabolism. Brown nodes : nucleotide and protein metabolism. Green nodes : lipid metabolism. Metabolism : Citric acid cycle enzymes Cycle Citrate synthase Aconitase Isocitrate dehydrogenase Oxoglutarate dehydrogenase Succinyl CoA synthetase Succinate dehydrogenase ( SDHA ) Fumarase Malate dehydrogenase and ETC Anaplerotic to acetyl - CoA Pyruvate dehydrogenase complex ( E1, E2, E3 ) ( regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase ) to α - ketoglutaric acid Glutamate dehydrogenase to succinyl - CoA Methylmalonyl - CoA mutase to oxaloacetate Pyruvate carboxylase Aspartate transaminase Mitochondrial electron transport chain / oxidative phosphorylation Primary Complex I / NADH dehydrogenase Complex II / Succinate dehydrogenase Coenzyme Q Complex III / Coenzyme Q - cytochrome c reductase Cytochrome c Complex IV / Cytochrome c oxidase Coenzyme Q10 synthesis : COQ2 COQ3 COQ4 COQ5 COQ6 COQ7 COQ9 COQ10A COQ10B PDSS1 PDSS2 Other Alternative oxidase Electron - transferring - flavoprotein dehydrogenase LCCN : sh85073260 GND : 4148058 - 2 Retrieved from `` https://en.wikipedia.org/w/index.php?title=Citric_acid_cycle&oldid=817440229 '' Categories : Biochemistry Cellular respiration Exercise physiology Metabolic pathways Citric acid cycle 1937 in biology Hidden categories : Wikipedia articles with LCCN identifiers Wikipedia articles with GND identifiers Talk Contents About Wikipedia Bân - lâm - gú Беларуская Български Bosanski Català Čeština Dansk Deutsch Eesti Ελληνικά Español Esperanto Euskara فارسی Français Galego 한국어 Հայերեն Hrvatski Bahasa Indonesia Íslenska Italiano עברית Кыргызча Latviešu Lëtzebuergesch Lietuvių Magyar Македонски മലയാളം Bahasa Melayu Nederlands 日本 語 Norsk Occitan پښتو Polski Português Română Русский Sicilianu Simple English Slovenčina Slovenščina کوردی Српски / srpski Srpskohrvatski / српскохрватски Basa Sunda Suomi Svenska Tagalog தமிழ் ไทย Türkçe Українська Tiếng Việt 粵語 中文 Edit links This page was last edited on 28 December 2017, at 11 : 22. 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Question: what is the rate limiting enzyme of kreb's cycle
Answer: Isocitrate dehydrogenase; Isocitrate dehydrogenase