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Abstract Detail

Plant Secondary Chemistry: from Biochemistry to Applications

Stout, Jake [1], Page, Jonathan [2].

Cannabinoid diversity in Cannabis sativa and the identification of cannabichromenic acid synthase using the cannabis genome.

Cannabis (Cannabis sativa L.) has been used by humans for millennia as a source of food, fibre and medicine. The medicinal properties of cannabis can largely be attributed to the cannabinoids, a group of prenylated polyketides that are only produced in this species. Many of these compounds exert their medicinal properties by acting as ligands to human GPCR receptors which modulate our endogenous endocannabinoid signaling system. The female flowers of marijuana strains predominantly accumulate tetrahydrocannabinolic acid (THCA). Upon heating, this metabolite spontaneously decarboxylates to tetrahydrocannabinol (THC), which is the cannabinoid that is responsible for the analgesic and psychotropic properties of cannabis. Hemp strains accumulate cannabidiolic acid (CBDA), which thermally degrades into cannabidiol (CBD). This compound has recently garnered a great deal of interest due to its anti-inflammatory, antiepileptic, antitumor and neuroprotective properties. To understand how cannabis produces these compounds, we sequenced the cannabis genome and transcriptome in 2012. Using these resources we ‘completed’ the pathway leading to the production of THCA and CBDA by identifying three genes which encode an acyl-activating enzyme, a novel polyketide cyclase, and a prenyltransferase. In addition to THCA and CBDA, cannabis produces over 100 other cannabinoids with different chemical structures. These cannabinoids are not as well pharmacologically-characterized as THC and CBD, and the biosynthetic enzymes that produce these compounds have not yet been identified. To identify new genes that contribute to the metabolic diversity in cannabis, we queried the cannabis genome to identify homologs of tetrahydrocannabinolic acid synthase (THCAS), which encodes an FAD-linked oxidoreductase that catalyzes synthesis of THCA from cannabigerolic acid (CBGA). In addition to the previously discovered cannabidiolic acid synthase which produces CBDA, six additional homologs were identified. These genes were cloned and expressed in Pichia pastoris. One of these genes was found to encode cannabichromenic acid synthase (CBCAS), which produces the fourth-most abundant cannabinoid in cannabis. This enzyme shares remarkable homology to THCAS and these enzymes likely produce their reaction products through a similar mechanism. Using the published THCAS crystal structure, comparisons of variant amino acid residues within the active sites of THCAS and CBCAS suggest that subtle changes in substrate binding and positioning results in the variation in carbon skeletons produced by these homologous enzymes.

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1 - University of Manitoba, Biological Sciences, 50 Sifton Road, Winnipeg, MB, R3T 2N2, Canada
2 - University of British Columbia, Botany, 3529-6270 University Blvd., Vancouver, BC, V6T 1Z4, Canada

plant secondary chemistry
natural compounds
cannabichromenic acid.

Presentation Type: Symposium Presentation
Session: SY01
Location: Hall C/The Shaw Conference Centre
Date: Monday, July 27th, 2015
Time: 8:15 AM
Number: SY01002
Abstract ID:510
Candidate for Awards:None

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