# Fermentation Strategies for Production of Pharmaceutical Ternenoids in Engineered Yeast
## 2 Pharmaceutical Terpenoids
### Cannabinoids  
Cannabinoids comprise a group of more than 100 prenylated phenolic compounds found in _Cannabis_ spp. (Cannabaceae), mainly in the plant _Cannabis sativa_. Apart from plant derivatives, Cannabinoids also involve Endocannabinoids, Phytocannabinoids, and Synthetic cannabinoids, which are able to bind to the human cannabinoid receptors [8; 34; 47]. Cannabinoid rich plants like _C. sativa_ and _C. indica_ have been used for different purposes for more than 5000 years. The fiber-type of Cannabis (hemp), which contains the major cannabinoid, cannabidiol (CBD) (Figure 4), has been often used in the treatment of pain relieving conditions. On the other side, \(\Delta\)9-tetrahydrocannabinol (THC) (Figure 4), found in high quantity in Cannabis (marijuana), has been known for psychoactive properties, and generally used as a recreational drug and in the treatment of several medical conditions [8; 48; 49]. In addition, many pharmaceutical companies have produced several synthetic cannabinoid drugs, known by different brand names, such as Cesamet (Valeant Pharmaceuticals North America, Bridgewater, NJ, USA), Marinol (Unimed Pharmaceuticals Inc., Marietta, GA, USA), and Sativex (GW Pharmaceuticals plc, Cambridge, UK). These drugs have been used in Canada, USA, UK, and other countries to treat nausea and vomiting caused by cancer chemotherapy, anorexia associated with weight loss in patients with AIDS, and symptomatic relief of neuropathic pain in multiple sclerosis [34; 50].  
Cannabinoids also called as terpenophenic in the class of meroterpene, are produced as secondary metabolite of Cannabis through concatenation of isoprenoid precursor with a second fatty acid derivative precursor by a prenyltransferase enzyme. This enzyme synthesizes cannabigerolic acid (CBGA), through the prenylation of olivetolic acid and geranyl diphosphate (GPP). CBGA is then converted into different cyclized compounds, such as tetrahydrooctannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA). Finally, these compounds undergo decarboxylation to produce biologically active compounds THC, CBD, and CBC, which are the main cannabinoids placed in _Cannabis_ spp. [2; 8; 34; 51].  
In recent years, _Cannabis_ spp. has been legally used for the medical treatments in many countries, such as USA, Canada, Israel, and several European countries including  
Figure 4: Chemical structure of \(\Delta\)9-tetrahydrocannabinol (THC) (**A**) and cannabidiol (CBD) (**B**).  
Figure 3: Chemical structure of Paclitaxel.  
the Netherlands, Germany, and the Czech Republic. However, _Cannabis_ spp. cannot be cultivated in several countries due to the legal issues. Agricultural production of cannabinoids via Cannabis cultivation has several disadvantages, such as low yield due to climate changes and plant diseases, low concentrations of cannabinoids in plant, necessity of extraction processes, and sociopolitical factors for the use of Cannabis, which has been mostly seen as a source of narcotics. On the other hand, chemical synthesis of cannabinoids does not offer an alternative production way because of synthesis complexity, which generally causes low yields and high production cost. For these reasons, microbial production of these compounds by engineered yeast would serve a sustainable, reliable, eco-friendly, and cost-effective alternative approach [2; 34].