Cannabinoid Biosynthesis Part 1 – CBG, THC, CBD, and CBC

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For decades growers have crossbred the best strains of cannabis they could find, logically, to produce another high potency strain. The psychoactive potency sought after is due to the production of specific cannabinoids, most notably THC (or Δ9-THC). Recently there has been a surge of interest in a larger variety of naturally occurring cannabinoids due to their important medicinal value. Some of the more abundant cannabinoids produced by Cannabis sativa are abbreviated CBGA, CBG, Δ9-THCA, CBDA, CBD, THCV, Δ8-THC, CBN, CBCA, and CBC. Where did this alphabet soup come from! What the heck are all these? Well, THC and all of the rest of the cannabinoids are produced in glands called trichomes (see photograph of trichomes above). A gland itself is an organ composed of a specialized type of cell that secretes some type of biologically produced chemical, for example, hormones or saliva. The cells of the trichomes produce and secrete the various cannabinoid molecules.

Cannabinoids are produced within the trichome cells through biosynthesis, in which enzymes catalyze a series of chemical reactions to produce complex molecules from simple (smaller) molecules. Biosynthesis is a truly amazing process that can be summarized in a few simple steps. For cannabinoid biosynthesis the three basic steps are binding, prenylation, and cyclization. On a molecular level what happens is: 1) nanoscale macromolecules called enzymes literally grab (bind) to one or two small molecules (substrates), 2) attach the substrates to each other (prenylation, catalytic chemical conversion of the substrates), and then 3) pass the small molecule (transformed substrate) down an assembly line to another enzyme that produce sequential changes to the small molecule (cyclization). I think of enzymes as biological nanomachines that use chemical energy rather than mechanical energy to build structures. Enzymes are truly fascinating and have inspired numerous studies in nanotechnology, biology, and other fields.

The details regarding biosynthesis of the various cannabinoids are well known and I will describe parts of it here in layman’s terms. The following figures depict some of the molecular structures involved in cannabinoid biosynthesis. In these figures, each line is a bond between atoms. When two lines meet at a point and no letter is written the atom is by default carbon. Oxygen, and phosphorus, atoms are explicitly indicated. Hydrogen atoms are only drawn in when bonded to oxygen or on the aromatic ring, they are not drawn on the alkyl chains. The curved arrows that point from one atom to another indicate that a new bond is formed between those atoms during the reaction, they also indicate the motion or exchange of electrons which make up a bond. Not all steps are shown, so there are some bonds that break and byproducts formed which are not shown.

The precursors to all natural cannabinoids, geranyl pyrophosphate and olivetolic acid, are produced themselves by a complex series of biosynthetic reactions I won’t cover here. Geranyl pyrophosphate and olivetolic acid combine (bond to one another) with the assistance of an enzyme in the prenyltransferase category known as GOT, thus creating the first cannabinoid, CBGA (see Figure 1). The CBGA contains a carboxylic acid group with the molecular formula COOH, and due to the presence of that acidic group, an “A” is placed at the end of CBGA. This is true for the rest of the cannabinoids whose acronym end with the letter A (e.g. THCA, CBDA, etc.). The carboxylic acid groups spontaneously break off of the cannabinoid structures as CO2 gas when heated, and thus CBGA becomes CBG when heated (and THCA –> THC, CBDA –> CBD etc.). This is considered a degradation process because it does not require enzymes and happens after the plant is harvested. The CBG type of cannabinoids have one ring in the molecular structure, it is the aromatic ring that came from the olivetolic acid (see Figure 1).

 

Figure 2. Biosynthesis of CBGA and decarboxylation to CBG. Note, all reaction steps are note shown and reactions are not balanced.

Figure 1. Biosynthesis of CBGA and decarboxylation to CBG. Note, all reaction steps are note shown and reactions are not balanced.

So CBGA is the first cannabinoid formed from a biosynthetic reaction, which joined two smaller pieces together; it is also the precursor to all other natural cannabinoids. Next, CBGA is cyclized into THCA, CBDA, or CBCA via the enzymes known as TCHA synthase, CBDA synthase, and CBCA synthase. The presence and relative quantities of the specific enzymes are what controls which cannabinoid is the major product from each particular strain, and each particular cell. As I mentioned before, the CBG type cannabinoids have only one ring in their structure. After the cyclization reactions the THCA, CBDA, and CBCA cannabinoids have more rings in their structures (see Figure 2). For THCA two new rings are formed by creation of two new covalent bonds, a carbon-oxygen bond and a carbon-carbon bond. The CBDA synthase enzyme catalyzes a reaction that creates one new carbon-carbon (C-C) bond at the same position that the C-C bond formed in THCA, but without the new C-O bond, thus forming CBDA. The formation of CBCA occurs by the formation of one carbon-oxygen bond at a different position of the molecule than the carbon-oxygen bond formed in THCA. Compounds with two rings fused to one another such as in CBCA and CBC are said to be bicyclic, but you can’t ride them, they’re much too small. Anyhow, that’s how THCA, CBDA, and CBCA are made through biosynthesis.

Figure 3. Cyclization of CBGA into the three cannabinoids THCA, CBDA, and CBCA followed by decarboxylation to produce THC, CBD, and CBC.

Figure 2. Cyclization of CBGA into the three cannabinoids THCA, CBDA, and CBCA followed by decarboxylation to produce THC, CBD, and CBC.

When typical bud is dried and cured properly without too much direct sunlight or heat the major product will be the acidic form of the cannabinoid (THCA, CBDA, CBCA or CBGA). When smoked or baked into edibles these molecules decarboxylate (decarboxylated forms might be produced to a small extent biosynthetically and while drying, but acidic forms are the major product). The decarboxylation products are Δ9-THC, CBD, and CBC (see Figure 2). Recall that the first cannabinoid mentioned here also decarboxylates to go from CBGA to CBG.

There are at least 100 natural cannabinoids reported in the scientific literature. In 2005, professors M. A. ElSohly and D. Slade from the University of Mississippi published a detailed review of the 70 known cannabinoids at that time. In the past 9 years ElSohly, Slade, and co-workers isolated and described about 28 new cannabinoid derivatives, and a couple have been reported by a group in Italy. Most of these new, exotic cannabinoids are produced in trace amounts, meaning that the scientists begin with hundreds of grams of marijuana and extract out only a few milligrams of some new cannabinoid derivative. There are even more synthetic cannabinoids to add to the list, commonly sold as “spice”. Probably due to the criminalization of cannabis, there has been a surge in the chemical synthesis of unnatural cannabinoids in attempt to mimic the high but allow users to pass drug tests for work, sports, or whatever. So as you can now appreciate, there are many more cannabinoids then the familiar compound, THC. What’s more interesting, the medicinal effects of these compounds in isolation and in various combinations and proportions are just now beginning to be studied and fully appreciated.

Photo at top courtesy of Gil Weedmaps and Ashley Duran

 

About Author

Anthony Burke earned simultaneous bachelor's degrees in chemistry and plant biology in 2004 from the College of Chemistry and College of Natural Resources at UC Berkeley. He went on to earn his PhD in chemistry at UC Irvine in 2011, with a focus on natural product synthesis and tandem mass spectrometry for proteomics research. Postdoctoral research in organic nanomaterials was also completed at UC Irvine in the Department of Chemical Engineering and Materials Science. He now works for Ghost Group as the Chief Scientific Officer.

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