# The Origin and Biomedical Relevance of Cannabigerol
## 4 Biosynthesis of Cannabigerol  
Cannabinoids present in plants are formed by biosynthesis from precursors in the form of the respective fatty acids or geranyl diphosphate (GPP) present within trichomes [13], with two possible mechanisms suggested as those leading to the formation of CBG (Figure 3). In the first mechanism, biosynthesis of cannabigerol occurs by direct synthesis from GPP and Olivetol (1,3-dihydroxy-5-pentylbenzene; OL), similarly to the synthetic production of CBG [30]. However, a more likely mechanism of CBG formation is thought to be the process of non-enzymatic decarboxylation of cannabigerolic acid (CBGA) formed from olivetolic acid (OLA) and geranyl diphosphate [8]. This approach seems more realistic due to the fact that Olivetol is not detected in _Cannabis sativa_ L. tissues despite the presence of olivetol synthase (OLS), an enzyme essential for its biosynthesis [31]. Another factor supporting the latter described mechanism of biosynthesis of cannabigerol is the fact that decarboxylation of CBGA and other phytocannabinoids synthesized in the acid form occurs by non-enzymatic means, including those occurring as a result of long-term storage, or under the influence of irradiation (from either sunlight and UV light) or increased temperature. At the same time, the lack of involvement of enzymes necessary for such a conversion  
Figure 2: Chemical structures of main compounds from the group of cannabigerol-type phytocannabinoids. explains the mode of action of orally ingested _Cannabis sativa_ L. in the form of heat-treated products (e.g., during the smoking of hemp cigarettes) [30]. Taking into account the details concerning cannabigerol biosynthesis, it was found that glucose produced through photosynthesis is converted to phosphoenolpyruvate, which--under the influence of pyruvate kinase and pyruvate dehydrogenase--is converted to acetyl-coenzyme A (acetyl-CoA) (Figure 4A). Acetyl-CoA is a key chemical that acts as a substrate in the formation of both geranyl diphosphate and malonyl-CoA, which are necessary for the formation of olivetolic acid and olivetol, i.e., the precursors of cannabigerolic acid [32] and cannabigerol, respectively [31]. Hexanoyl-CoA, on the other hand, is formed during the action of hexanoyl-CoA synthase on hexanoic acid formed in the process of biosynthesis of fatty acid [33]. The aldol condensation of hexanoyl-CoA and malonyl-CoA (ratio 1:3) in the presence of olivetolic acid cyclase (OLAC) results in the formation of olivetolic acid [32], whereas in the presence of olivetol synthase (OLS), decarboxylation with simultaneous cyclization results in the formation of olivetol [31]. As a result of numerous transformations, Acetyl-CoA is initially converted to mevalonic acid (MVA), which is then converted to geranyl diphosphate under the influence of kinases, decarboxyl  
Figure 3: Biosynthesis of CBG including both direct synthesis and the formation of cannabigerol by non-enzymatic decarboxylation of cannabigerol acid [30; 31]. Under the action of the respective enzymes (THCAS tetrahydroccannabinolic acid synthase and CBDAS cannabidiolic acid synthase), the resulting cannabigerolic acid is converted to \(\Delta^{9}\)-tetrahydrocannabinolic acid and cannabidiolic acid (Figure 4B), which are then decarboxylated to form \(\Delta^{9}\)-THC and CBD, respectively [36; 37]. Due to its easy conversion to CBD, cannabigerol is treated as a structural analogue of CBD with an open cyclohexylene ring [38]. Figure 4: Biosynthesis of olivetolic acid and geranyl diphosphate (**A**) and their further transformations leading to the formation of cannabigerolic acid, including the conversion of CBGA to cannabigerol, cannabidiolic acid, cannabichromenic acid, and \(\Delta^{9}\)-tetrahydrocannabinolic acid (**B**) [8; 30; 31]. The content of cannabinoid in _Cannabis sativa_ L. is very low (up to approx.