By Allan Mai ‘20

Scientists have recently been exploring routes to biosynthesize cannabinoids by introducing a series of genes into yeast cells. Using the simple sugar galactose, Dr. Xiaozhou Luo and his team at the University of California at Berkeley successfully devised a pathway to produce major cannabinoids such as cannabigerolic acid and cannabidiolic acid among others. The biosynthesis of such compounds would allow for more rigorous studies to be conducted on potential clinical uses for cannabinoids.

The method employed by Dr. Luo and his team involved the creation of olivetolic acid, one of the intermediates in the synthesis pathway. To do this, genes CsTKS and CsOAC were introduced into S. cerevisiae to generate yCAN01, allowing the cells to manufacture olivetolic acid from malonyl-CoA and hexanoyl-CoA; this new strain can generate 0.2 mg of olivetolic acid from galactose. Cannabigerolic acid and cannabidiolic acid were subsequently produced from the olivetolic acid and geranyl pyrophosphate with the help of an enzyme known as geranyl pyrophosphate olivetolic geranyltransferase (GOT). To improve the yield of the intended product, the researchers tried to identify potential limiting factors in the biosynthetic pathway by overexpressing the CsTKS and CsOAC genes. The new strain, as expected, yielded a threefold increase in the intermediates needed for the reaction; however, the cannabinoid reaction remained essentially unchanged. This suggests that the conversion of the intermediates into malonyl-CoA and hexanoyl-CoA from olivetolic acid has an additional limiting factor that requires further investigation.

Although cannabis receives a disproportionate amount of media attention, other potentially useful forms of cannabinoids exist. There is, for example, exciting research underway regarding the effects of endocannabinoids, which are lipid compounds that interact with specific receptors in the brain; in fact, many forms of cannabinoids have been approved for medicinal use in countries around the world. Dr. Luo’s method of synthesizing cannabinoids from yeast and galactose may be the first step in making these medicinal compounds more readily available.
References

1. X. Luo, et. al., Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature 567, 123-126 (2019). doi: 10.1038/s41586-019-0978-9.
   
2. Image retrieved from: https://www.pexels.com/photo/shallow-focus-photography-of-cannabis-plant-606506/