Cannabis sativa contains a variety of unique secondary metabolites, called cannabinoid. Among them, tetrahydrocannabinol has been well known to be the psychoactive principle of this plant, while cannabidiol and cannabichromene, which do not exert psychotropic effects, possess interesting pharmacological activities. Thus, cannabinoids have attracted considerable attention, whereas the biosynthesis of these cannabinoids has remained mostly unclear. To reveal the mechanism of cannabinoid biosynthesis, their biosynthetic enzymes were investigated. Consequently, we identified three cannabinoid synthases (tetrahydrocannabinolic acid synthase, cannabidiolic acid synthase and cannabichromenic acid synthase) that catalyze the oxidocyclization of cannabigerolic acid to tetrahydrocannabinolic acid, cannabidiolic acid and cannabichromenic acid, and subsequently purified them to homogeneity. These cannabinoid synthases are the first enzymes involved in cannabinoid biosynthesis to be purified and identified. All cannabinoid synthases catalyze oxidocyclization of cannabigerolic acid without any cofactors and coenzymes and display higher enzyme activity for cannabigerolic acid than for its Z-isomer cannabinerolic acid. These results indicate that tetrahydrocannabinolic acid, cannabidiolic acid and cannabichromenic acid are predominantly biosynthesized from cannabigerolic acid.
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