Heterologous production of Cannabis sativa-derived specialised metabolites of medicinal significance - Insights into engineering strategies

Danielle Wiles; Bhuvana K Shanbhag; Martin O'Brien; Monika S Doblin; Antony Bacic; Travis Beddoe

doi:10.1016/j.phytochem.2022.113380

Heterologous production of Cannabis sativa-derived specialised metabolites of medicinal significance - Insights into engineering strategies

Phytochemistry. 2022 Nov:203:113380. doi: 10.1016/j.phytochem.2022.113380. Epub 2022 Aug 30.

Authors

Danielle Wiles¹, Bhuvana K Shanbhag¹, Martin O'Brien¹, Monika S Doblin², Antony Bacic², Travis Beddoe³

Affiliations

¹ Department of Animal, Plant and Soil Sciences and AgriBio Centre for AgriBioscience, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3083, Australia; Australian Research Council Research Hub for Medicinal Agriculture, AgriBio Centre for AgriBioscience, La Trobe University, Bundoora, VIC, 3086, Australia.
² Department of Animal, Plant and Soil Sciences and AgriBio Centre for AgriBioscience, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3083, Australia; Australian Research Council Research Hub for Medicinal Agriculture, AgriBio Centre for AgriBioscience, La Trobe University, Bundoora, VIC, 3086, Australia; La Trobe Institute for Agriculture & Food, Department of Animal, Plant and Soil Science, AgriBio Centre for AgriBioscience, La Trobe University, Bundoora, VIC, Australia.
³ Department of Animal, Plant and Soil Sciences and AgriBio Centre for AgriBioscience, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, 3083, Australia; Australian Research Council Research Hub for Medicinal Agriculture, AgriBio Centre for AgriBioscience, La Trobe University, Bundoora, VIC, 3086, Australia. Electronic address: t.beddoe@latrobe.edu.au.

PMID: 36049526
DOI: 10.1016/j.phytochem.2022.113380

Abstract

Cannabis sativa L. has been known for at least 2000 years as a source of important, medically significant specialised metabolites and several bio-active molecules have been enriched from multiple chemotypes. However, due to the many levels of complexity in both the commercial cultivation of cannabis and extraction of its specialised metabolites, several heterologous production approaches are being pursued in parallel. In this review, we outline the recent achievements in engineering strategies used for heterologous production of cannabinoids, terpenes and flavonoids along with their strength and weakness. We provide an overview of the specialised metabolism pathway in C. sativa and a comprehensive list of the specialised metabolites produced along with their medicinal significance. We highlight cannabinoid-like molecules produced by other species. We discuss the key biosynthetic enzymes and their heterologous production using various hosts such as microbial and eukaryotic systems. A brief discussion on complementary production strategies using co-culturing and cell-free systems is described. Various approaches to optimise specialised metabolite production through co-expression, enzyme engineering and pathway engineering are discussed. We derive insights from recent advances in metabolic engineering of hosts with improved precursor supply and suggest their application for the production of C. sativa speciality metabolites. We present a collation of non-conventional hosts with speciality traits that can improve the feasibility of commercial heterologous production of cannabis-based specialised metabolites. We provide a perspective of emerging research in synthetic biology, allied analytical techniques and plant heterologous platforms as focus areas for heterologous production of cannabis specialised metabolites in the future.

Keywords: Cannabaceae; Cannabinoids; Cannabis sativa; Flavonoids; Heterologous production; Metabolic engineering; Protein engineering; Terpenes.

Publication types

Review

MeSH terms

Cannabinoids* / metabolism
Cannabis* / genetics
Cannabis* / metabolism
Flavonoids / metabolism
Metabolic Engineering / methods
Terpenes / metabolism

Substances

Cannabinoids
Flavonoids
Terpenes