Cannabinoid synthase: the enzymes that decide the chemotype

In short

A cannabinoid synthase is an enzyme that turns cannabigerolic acid into one of the three acid precursors. There are three of them: THCA synthase, CBDA synthase and CBCA synthase. Which one is active in a plant sets its chemotype and therefore whether it accumulates THC, CBD or cannabichromene.

What they do chemically

All three catalyse the same kind of reaction: an oxidative cyclisation of the geranyl group on the CBGA molecule. The only difference is where the ring closes, and that alone produces the different outcomes.

They are covalently flavinylated oxidases, enzymes carrying a firmly bound flavin cofactor. That places them in the family around the berberine bridge enzyme, with which they share 40 to 50 % of their amino acid sequence.

Why the switch is not clean

THCA and CBDA synthase share 83.9 % identity across 544 amino acids and evidently descend from a common ancestor. That closeness has consequences: expressed in yeast, both enzymes produced all three major cannabinoids from cannabigerolic acid, along with five further unidentified products carrying a cannabinoid scaffold.

The picture of one enzyme with exactly one product does not survive measurement in the test tube. What sets the chemotype is the relative activity of the enzymes, not their exclusivity.

Relevance to cannabis

When a synthase fails, its substrate piles up. That is the mechanism behind chemotype IV: a variant of THCA synthase carrying a single base substitution, probably leaving the enzyme unable to work, so cannabigerolic acid remains in the plant. Breeders use that substitution as a molecular marker. What it means for CBG content is covered in the article on cannabigerol.

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