Synthetic Biology of Cannabinoids and Cannabinoid Glucosides in Nicotiana benthamiana and Saccharomyces cerevisiae

Phytocannabinoids are a group of plant-derived metabolites that display a wide range of psychoactive as well as health-promoting effects. The production of pharmaceutically relevant cannabinoids relies on extraction and purification from cannabis (Cannabis sativa) plants yielding the major constitue...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2020-10, Vol.83 (10), p.2877-2893
Main Authors: Gülck, Thies, Booth, J. K, Carvalho, Â, Khakimov, B, Crocoll, C, Motawia, M. S, Møller, B. L, Bohlmann, J, Gallage, N. J
Format: Article
Language:English
Subjects:
Cannabidiol
Cannabinoids - metabolism
Cannabis
Dronabinol
Glucosides - metabolism
Metabolic Engineering
Molecular Structure
Nicotiana - physiology
Plant Proteins
Saccharomyces cerevisiae - physiology
Salicylates
Synthetic Biology
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Summary:Phytocannabinoids are a group of plant-derived metabolites that display a wide range of psychoactive as well as health-promoting effects. The production of pharmaceutically relevant cannabinoids relies on extraction and purification from cannabis (Cannabis sativa) plants yielding the major constituents, Δ9-tetrahydrocannabinol and cannabidiol. Heterologous biosynthesis of cannabinoids in Nicotiana benthamiana or Saccharomyces cerevisiae may provide cost-efficient and rapid future production platforms to acquire pure and high quantities of both the major and the rare cannabinoids as well as novel derivatives. Here, we used a meta-transcriptomic analysis of cannabis to identify genes for aromatic prenyltransferases of the UbiA superfamily and chalcone isomerase-like (CHIL) proteins. Among the aromatic prenyltransferases, CsaPT4 showed CBGAS activity in both N. benthamiana and S. cerevisiae. Coexpression of selected CsaPT pairs and of CHIL proteins encoding genes with CsaPT4 did not affect CBGAS catalytic efficiency. In a screen of different plant UDP-glycosyltransferases, Stevia rebaudiana SrUGT71E1 and Oryza sativa OsUGT5 were found to glucosylate olivetolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid. Metabolic engineering of N. benthamiana for production of cannabinoids revealed intrinsic glucosylation of olivetolic acid and cannabigerolic acid. S. cerevisiae was engineered to produce olivetolic acid glucoside and cannabigerolic acid glucoside.
ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.0c00241