Medical Research

An Explanation of Cannabidiolic Acid (CBDA) Synthase

Written by Denise Recalde

Cannabidiolic acid (CBDA) synthase is the biological enzyme responsible for catalyzing the oxidocyclization of cannabigerolic acid (CBGA) into CBDA in the fiber-type Cannabis sativa L. [1] CBDA dominates as a cannabinoid constituent in the plant.

The activating enzyme features only a single polypeptide and is similar to the NH2-terminal amino acid sequence of Delta1-tetrahydrocannabinolic-acid synthase.

In order to trigger the oxidocyclization reaction, CBDA synthase does not need to have molecular oxygen, coenzymes, metal ion cofactors, or hydrogen peroxide. This means that CBDA synthase cannot be classified as either a peroxidase or oxygenase — indeed, it’s enzymatic cyclization moves forward without oxygenated intermediates.

CBDA is mostly biosynthesized from cannabigerolic acid, more so than cannabinerolic acid.

Reseachers have found, through CDNA encoding by polymerase-based chain reactions with gene-specific and degenerate primers, by reverse transcription and by a biochemical identification of the recombinant enzyme, that CBDA synthase is a covalently flavinylated oxidase. [2]

The functional and structural properties of the synthase are highly akin to those of tetrahydrocannabinolic-acid (THCA) synthase, which biosynthesizes THCA, a cannabinoid in Cannabis plants that give way to drugs.

Along with THCA synthase, CBDA synthase, with three products still not identified, form five major cannibinoids of Cannabis sativa L. That is, geranylpyrophosphate, olivetolate geranyltransferase,  THCA, CBDA and cannabichromenic acid (CBCA). [3]

These cannabinoids are well known and their pharmacological properties have been studied by many a team of researchers. The biosynthetic enzymes are purified from young quickly expanding plant leaves of C. sativa. [4]

The functional, structural, and genetic link between THCA synthase and CBDA synthase is of much interest to scientists. Similar with the substrate CBGA, the two enzymes catalyze oxidocyclization reactions, as has already been mentioned above.

In one study, scientists aligned the amino acid sequences of the two synthases and concluded that the structure of CBDA synthase has high level of homology to that of THCA synthase. Indeed, an 84% identity in a 544-amino acid overlap.

This identity proves an evolutional relationship between the two enzymes, and indicates that the two synthases derived from a common ancestor.

The two chemotype-determining cannabinoids, are biosynthesized with mechanisms of similar reaction in both drug-type and fiber-type Cannabis plants. The two enzymes seem widely distributed in the plant kingdom. [5]



[1] Taura F, Morimoto S, Shoyama Y. Taura F, et al. Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L.. Biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid. J Biol Chem. 1996 Jul 19;271(29):17411-6. doi: 10.1074/jbc.271.29.17411.


[2] Taura F, Sirikantaramas S, Shoyama Y, Yoshikai K, Shoyama Y, Morimoto S. Taura F, et al. Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa. FEBS Lett. 2007 Jun 26;581(16):2929-34. doi: 10.1016/j.febslet.2007.05.043. Epub 2007 May 25.


[3] Zirpel B, Kayser O, Stehle F. Zirpel B, et al. Elucidation of structure-function relationship of THCA and CBDA synthase from Cannabis sativaL. J Biotechnol. 2018 Oct 20;284:17-26. doi: 10.1016/j.jbiotec.2018.07.031. Epub 2018 Jul 24.


[4] Sirikantaramas S, Taura F, Morimoto S, Shoyama Y. Sirikantaramas S, et al. Recent advances in Cannabis sativa research: biosynthetic studies and its potential in biotechnology. Curr Pharm Biotechnol. 2007 Aug;8(4):237-43. doi: 10.2174/138920107781387456.


[5] Aryal, N., Orellana, D.F. & Bouie, J. Distribution of cannabinoid synthase genes in non-Cannabis organisms. J Cannabis Res 1, 8 (2019)

About the author

Denise Recalde