The Mother Cannabinoid

By Dr. Daniela Vergara

In this post, I’m going to tell you about my favorite cannabinoid, CBGA, and explain why it’s my top pick.

The Cannabinoid Biochemical Pathway
The biochemical process responsible for forming the cannabinoids we know, such as CBDA (cannabidiolic acid), THCA (tetrahydrocannabinolic acid), and CBCA (cannabichromenic acid), is a complex and lengthy one. Early in this pathway, it connects with the same metabolic route that produces terpenes, which are some of the compounds that give plants their smell.

As we mentioned in another article, the Cannabis sativa plant makes these cannabinoids in their acidic form. When you heat them, a chemical process called decarboxylation happens, which changes them into their neutral form [1]. This means the cannabinoids lose a carboxyl group (COOH), and turn into CBD (cannabidiol), THC (tetrahydrocannabinol), and CBC (cannabichromene) as we discussed in a previous post.

These neutral forms of cannabinoids interact more strongly with our body’s endocannabinoid system [2]. That’s why we smoke, vape, or cook cannabis—to activate the cannabinoids through heat.

An enzyme is a special kind of protein made by living things that helps speed up chemical reactions. You can think of an enzyme like a helper or a tiny machine that makes things happen faster—like breaking down food or building important molecules. There are many enzymes involved in the cannabinoid pathway, for example THCA Synthase which makes THCA, CBDA Synthase which makes CBDA, and CBCA Synthase which makes CBCA (Figure 1)

The marijuana plant makes cannabinoids in their acidic form. When heated, they change into their neutral form through a process called decarboxylation, where they lose a carboxyl group (COOH). This decarboxylation happens outside of the plant. In other words, the plant makes the acidic compounds, and heating them turns them into their neutral form. This is why in Figure 1 this step is called a “non-enzymatic conversion” because in this step these synthases are not needed. Figure 1 shows the last two steps of a much longer process that happens inside the plant.

_{Figure 1. Final steps of the metabolic pathway that produces well-known cannabinoids like THCA and CBDA. The enzyme CBGA synthase turns geranyl diphosphate into cannabigerolic acid (CBGA), which is the “mother” molecule used by the enzymes THCA synthase, CBDA synthase, and CBCA synthase to make THCA, CBDA, and CBCA. When heated, these three compounds—and CBGA itself—go through decarboxylation and change into their neutral forms: THC, CBD, CBC, and CBG. This decarboxylation step happens outside of the plant, which is why its called a “non-enzymatic conversion.” Figure modified from references [3-6]}

Promiscuous and Sloppy: The Party Enzymes!

In Figure 1, you can see that there are many enzymes involved and the ones mentioned here are called synthases because they help make certain compounds.

One important enzyme is CBGA synthase. It turns a basic building block called geranyl diphosphate into CBGA (cannabigerolic acid), which is the starting point for making many cannabinoids.

Then we have THCA synthase, CBDA synthase, and CBCA synthase—enzymes that turn CBGA into THCA, CBDA, and CBCA. These are known as cannabinoid oxidocyclases. The term “cannabinoid oxidocyclases” (which I love!) comes from a 2021 paper by van Velzen and Schranz [7]. I recommend checking it out. Another day, when we dive deeper into biochemistry, I’ll explain why they’re adopting this term “oxidocyclases”, which I consider very appropriate.

Even though enzymes are usually somewhat specific (perhaps you have heard of a key that only fits one lock), these ones are not. Each of these enzymes can actually make up to eight different compounds, not just the one they’re named after [8]. For example, THCA synthase can also make CBDA and CBCA. Because they’re not very precise, they are called sloppy enzymes. The sloppiest one might be the CBCA synthase, but we’ll save that story for later.

Since all three enzymes work on the same starting molecule (CBGA), and each one can make more than just one product, they are also considered promiscuous—that just means they have many possible “partners” in a reaction.

So basically, these enzymes are out there partying, mixing it up, and making all kinds of different compounds.

Do Hemp Rules Really Make Sense?

It’s very likely that the people who created the laws about hemp and marijuana didn’t know how these enzymes in the plant actually work, and that many enzymes can make a single compound (as we mentioned above these enzymes are sloppy and promiscuous). If they had known, maybe they wouldn’t have set the THC limit so low at 0.3%, or maybe they wouldn’t have set a limit at all. This lack of understanding about the plant’s biology and chemistry has caused problems for growers, producers, and breeders. Does this 0.3% THC rule actually make sense based on what we now know about the plant?

The Mother Cannabinoid

CBGA is often called the “mother cannabinoid” because it’s the starting point for several other cannabinoids. As shown in Figure 1 and mentioned earlier, the enzymes THCA synthase, CBDA synthase, and CBCA synthase all act on CBGA to form THCA, CBDA, and CBCA. Since all three depend on CBGA to form these important compounds (and possibly others), is often called the “mother cannabinoid”.  That’s one reason I really like CBGA—because as a mom myself, I relate to its central, nurturing role.

What Makes the Mother Cannabinoid’s Gene So Interesting

Something that fascinates me about the gene for CBGA synthase is how it’s built. This gene has a lot of exons and introns [9]. Exons are the parts of a gene that contain the instructions to make proteins. Introns are also part of the gene, but they don’t code for proteins. When a protein is made, only the exons are used.

What’s interesting here is that some of the introns in this gene are really big—up to 11,000 base pairs (those are the letters that make up DNA). While introns this big have been seen before, it’s not very common. Also, this gene has many introns—nine, ten, even eleven in some cases! That means it’s made up of lots of separate pieces. The gene for CBGA synthase also has many exons, which are the parts used to make proteins. Having more of them could allow the gene to make different versions of proteins.

This is another reason I like CBGA so much. Even though more research is needed to confirm this idea, it’s possible that the gene can make different protein structures, making it flexible, generous, and adaptable. Just like many moms are.

Possible Therapeutic Uses of CBG

As shown in Figure 1, the plant makes CBGA in its acidic form, called cannabigerolic acid. When it’s heated, just like THCA or CBDA, it goes through decarboxylation and turns into CBG (cannabigerol).

Like other cannabinoids, CBGA and CBG may have therapeutic benefits, but more research is needed to understand how well they work.

So far, studies suggest that CBGA and CBG might:

• Protect the brain -neuroprotective effects- [10]
• Help fight cancer -anticancer properties [11]
• Be useful in treating epilepsy [12]

However, many of these studies have only been done in mice, so more research is needed in humans.

I hope I’ve convinced you that the mother cannabinoid is the coolest of them all! CBGA is an amazing example of an important and helpful cannabinoid. It may have medical uses, could possibly form different kinds of proteins, and it’s essential for making the other major cannabinoids in the plant.

References

1. Hart, C.L., et al., Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology, 2001. 25(5): p. 757-765.
2. Gertsch, J., et al., Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences, 2008. 105(26): p. 9099-9104.
3. Page, J.E. and J.M. Stout, Cannabichromenic acid synthase from Cannabis sativa. 2017, Google Patents.
4. Vergara, D., et al., Gene copy number is associated with phytochemistry in Cannabis sativa. AoB PLANTS, 2019. 11(6): p. plz074.
5. Gülck, T. and B.L. Møller, Phytocannabinoids: origins and biosynthesis. Trends in plant science, 2020. 25(10): p. 985-1004.
6. Innes, P.A. and D. Vergara, Genomic description of critical upstream cannabinoid biosynthesis genes. bioRxiv, 2022: p. 2022.12. 15.520586.
7. van Velzen, R. and M.E. Schranz, Origin and evolution of the cannabinoid oxidocyclase gene family. Genome Biology and Evolution, 2021. 13(8): p. evab130.
8. Zirpel, B., O. Kayser, and F. Stehle, Elucidation of structure-function relationship of THCA and CBDA synthase from Cannabis sativa L. Journal of biotechnology, 2018. 284: p. 17-26.
9. Innes, P.A. and D. Vergara, Genomic description of critical cannabinoid biosynthesis genes. Botany, 2023.
10. Valdeolivas, S., et al., Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice. Neurotherapeutics, 2015. 12(1): p. 185-199.
11. Borrelli, F., et al., Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis, 2014: p. bgu205.
12. Anderson, L.L., et al., Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy. British journal of pharmacology, 2021. 178(24): p. 4826-4841.