Cannabinoids on the rise

Nature 567, 123–126 (2019)

Cannabinoids, such as Δ⁹-tetrahydrocannbinol (THC) and cannabidiol (CBD), are of potential pharmaceutical interest, but they are produced at relatively low levels by their native plant hosts. To address this limitation, Luo and Reiter et al. engineered yeast strains to produce multiple advanced cannabinoids from galactose. The intermediate olivetolic acid (OA) was first produced via the expression of a hexanoyl-CoA biosynthetic pathway, a tetraketide synthase, and an olivetolic acid cyclase. Upregulation of the mevalonate pathway and screening of candidate prenyltransferases then enabled the biosynthesis of cannabigerolic acid (CBGA) from OA and geranyl pyrophosphate (GPP). Finally, the inclusion of a cannabinoid synthase, followed by heat-induced decarboxylation, produced the mature THC or CBD. Capitalizing on the promiscuity of certain enzymes, supplying alternate fatty acids enabled the production of additional cannabinoid analogs with varied acyl chains. The establishment of this cannabinoid expression platform enables the facile production of both natural and synthetic cannabinoids for potential future medicinal studies.