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Illustration courtesy of Brian Ball
Biosynthesis and Degradation of Cannabinoids Part 2 THCV 8THC and CBN
The biosynthesis of THC and other cannabinoids occurs within glandular organs on the cannabis plant surface called trichomes. Within trichomes’ cells, enzymes build large complex molecules from smaller molecules through chemical bonding. The steps in the biosynthesis of cannabinoids can be described as: substrate binding, prenylation, and cyclization. Additionally, degradation reactions occur, such as decarboxylation and isomerization. All cannabinoid biosynthesis begins with prenylation, forming either CBGA, CBGVA or other CBG derivatives. Various cyclization and isomerization pathways, catalyzed by specific enzymes, lead to the multitude of cannabinoid structures. The figures used to show these molecular structures are described in the introduction of part 1.
The introduction of part 1 mentioned CBN, Δ8-THC and THCV, their formation is described here in part 2. The Δ8-THC derivative arises from a change in the position where the double bond (=) resides within the Δ9-THC structure (see Figure 1). Transformations with changes in the position of one or more double bonds are one example of isomerization reactions. For these types of reactions the molecular formula (total number of carbons, hydrogens, oxygens, and other atoms) is the same but the structure is different due to any change in the bonding arrangement. In this case the isomerization is not caused by an enzyme but occurs spontaneously and is considered degradation. Formation of CBN occurs through degradation of either Δ9-THC or Δ8-THC. The degradation reaction removes 4 hydrogen atoms (see Figure 1) and introduces more double bonds (=) in the second ring formed during biosynthesis. This is where the prefix “tetrahydro” comes from in the name of THC. If the 4 hydrogens were added back to cannabinol (CBN), then you get “tetrahydro”-cannabinol. This naming convention is presumably due to the fact that CBN was actually isolated first from cannabis, back around 1945 and was initially thought to be the psychoactive component. When there are three double bonds (=) in a 6-membered ring, the structure is said to be aromatic, but is not necessarily related to an increase in the compound’s aroma. The relative quantities of THCA, THC, and CBN in a bud can be used to approximate the age of a bud.
Finally, there is THCV. The story behind this recently appreciated cannabinoid goes all the way back to the first steps in cannabinoid synthesis: substrate binding and prenylation. Recall that the first cannabinoid described in part 1 was formed by the combination of the substrates olivetolic acid and geranyl pyrophosphate. Well, there is another molecule that is very similar to olivetolic acid but rather than having a C5H11 (n-pentyl) group coming off of the aromatic ring, it has a C3H7 (n-propyl) group (see Figure 2A).
This derivative of olivetolic acid is called divarinolic acid and it is formed through the same pathway as olivetolic acid but using a different substrate. When the substrates divarinolic acid and geranyl pyrophosphate bind to the GOT prenyltransferase, CBGVA is formed (see Figure 2B and the illustration at the top). CBGVA can cyclize in the same manner as CBGA and can thus lead to 3 more classes of cannabinoids, the THCVAs, the CBDVAs, and the CBCVAs. Each of these decarboxylate as described in part 1 and lead to THCV, CBDV, and CBCV (see figure 2B showing THCV). For every class of cannabinoid structure there are members bearing the C3H7 (n-propyl) group that have been observed, indicating that CBGVA reacts with all of the same enzymes as CBGA.
There are at least 100 natural cannabinoids reported in the scientific literature, as described in part 1. There is currently a surge of interest in the medicinal effects of the multitude of natural cannabinoids, along with terpenoids both in isolation and in various combinations and proportions. This research will likely spur a revolution in medicinal cannabis use.
If you missed out on “Cannabinoid Biosynthesis Part 1 – CBG, THC, CBD, and CBC”, click here to catch up.