Complete biosynthesis of cannabinoids and their unnatural analogues in yeast

  title={Complete biosynthesis of cannabinoids and their unnatural analogues in yeast},
  author={Xiaozhou Luo and Michael A. Reiter and Leo d’Espaux and Jeff Y F Wong and Charles M. Denby and Anna Lechner and Yunfeng Zhang and Adrian T. Grzybowski and Simon Harth and Weiyin Lin and Hyunsu Lee and Changhua Yu and John Shin and Kai Deng and Veronica Teixeira Benites and George Wang and Edward E K Baidoo and Yan Chen and Ishaan Dev and Christopher J. Petzold and Jay D. Keasling},
Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia1. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications2. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments3. However, the study and medicinal use of cannabinoids has been hampered by the legal… 
Distribution of cannabinoid synthase genes in non-Cannabis organisms
Comparative transcriptomic and metabolomic studies for mulberry and Cannabis plants could provide a much clear concepts on the co-evolution of these syanthases and in-depth bioinformatics and functional analysis of the enzymes involved are required for pharmaceutical research and industrial advancement.
Synthetic Biology of Cannabinoids and Cannabinoid Glucosides in Nicotiana benthamiana and Saccharomyces cerevisiae.
A meta-transcriptomic analysis of cannabis was used to identify genes for aromatic prenyltransferases of the UbiA superfamily and chalcone isomerase-like (CHIL) proteins and showed CBGAS activity in both N. benthamiana and S. cerevisiae.
Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses
Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders.
Biosynthesis of Nature-Inspired Unnatural Cannabinoids
The biosynthetic pathways of phytocannabinoids and synthetic biology efforts in producing them in heterologous hosts are summarized and detailed mechanistic insights are discussed in each part of the pathway in order to explore strategies for creating novel cannabinoids.
Comprehending and improving cannabis specialized metabolism in the systems biology era.
Recent advances in cannabinoid biochemistry and biotechnology
This review introduces the history of cannabinoid biosynthesis studies, and focuses on the biotechnological applications of biosynthetic enzymes.
A Synthetic Biochemistry Platform for the Enzymatic Synthesis of Cannabinoids and Other Prenylated Natural Products
This work tests an alternative approach to bio-based cannabinoid production using cell-free enzymatic synthesis, an approach the authors call synthetic biochemistry.
Cannabinomics: Application of Metabolomics in Cannabis (Cannabis sativa L.) Research and Development
Cannabis research is still in its infancy, and it is highly foreseen that the employment of advanced metabolomics will provide insights that could assist the sector to face the aforementioned challenges.
The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems
This review summarizes the biosynthesis of major phytocannabinoids in detail, the most recent development of their metabolic engineering in various systems, and the engineering approaches and strategies used to increase the yield.
Terpenes in Cannabis sativa - From plant genome to humans.
  • J. Booth, J. Bohlmann
  • Biology
    Plant science : an international journal of experimental plant biology
  • 2019


Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides
This work shows that a type III PKS (tetraketide synthase) from cannabis trichomes requires the presence of a polyketide cyclase enzyme, olivetolic acid cyclase (OAC), which catalyzes a C2–C7 intramolecular aldol condensation with carboxylate retention to form OA.
The draft genome and transcriptome of Cannabis sativa
The availability of the Cannabis sativa genome enables the study of a multifunctional plant that occupies a unique role in human culture and will aid the development of therapeutic marijuana strains with tailored cannabinoid profiles and provide a basis for the breeding of hemp with improved agronomic characteristics.
Purification and Characterization of Cannabidiolic-acid Synthase from Cannabis sativa L.
It is concluded that CBDA is predominantly biosynthesized from cannabigerolic acid rather than cannabinerolic acid, although the kcat for the former is lower than that for the latter, and that the enzymatic cyclization does not proceed via oxygenated intermediates.
The hexanoyl-CoA precursor for cannabinoid biosynthesis is formed by an acyl-activating enzyme in Cannabis sativa trichomes.
It is suggested that CsAAE1 may have been recruited to the cannabinoid pathway through the loss of its PTS1, thereby redirecting it to the cytoplasm and suggesting that hexanoate may be formed through a pathway that involves the oxygenation and breakdown of unsaturated fatty acids.
The Medicinal Use of Cannabis and Cannabinoids—An International Cross-Sectional Survey on Administration Forms
The survey was completed by 953 participants from 31 countries, making this the largest international survey on a wide variety of users of cannabinoid-based medicine performed so far, and in general, herbal non-pharmaceutical CBMs received higher appreciation scores by participants than pharmaceutical products containing cannabinoids.
Production of Δ9-tetrahydrocannabinolic acid from cannabigerolic acid by whole cells of Pichia (Komagataella) pastoris expressing Δ9-tetrahydrocannabinolic acid synthase from Cannabis satival.
Whole cells of P. pastoris offer the capability of synthesizing pharmaceutical THCA production using whole cells, which prevents the THCAS application in aqueous cell-free systems.
The inheritance of chemical phenotype in Cannabis sativa L. (V): regulation of the propyl-/pentyl cannabinoid ratio, completion of a genetic model
Inbred lines derived from multi-cross hybrid combinations reached unprecedented PC3 levels of up to 96 % which supports the hypothesis of the regulation of C3/C5 ratios, and a model of a multiple locus A1–A2–…An is proposed, with the pentyl- and propyl cannabinoid pathway being enhanced by alleles Ape1−n and Apr1–n, respectively.
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
A comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy is provided.