Biosynthetic origins of unusual cannabimimetic phytocannabinoids in Cannabis sativa L: A review

Plants of Cannabis sativa L. (Cannabaceae) produce an array of more than 160 isoprenylated resorcinyl polyketides, commonly referred to as phytocannabinoids. These compounds represent molecules of therapeutic importance due to their modulation of the human endocannabinoid system (ECS). While understanding of the biosynthesis of the major phytocannabinoids Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) has grown rapidly in recent years, the biosynthetic origin and genetic regulation of many potentially therapeutically relevant minor phytocannabinoids remains unknown, which limits the development of chemotypically elite varieties of C. sativa. This review provides an up-to-date inventory of unusual phytocannabinoids which exhibit cannabimimetic-like activities and proposes putative metabolic origins. Metabolic branch points exploitable for combinatorial biosynthesis and engineering of phytocannabinoids with augmented therapeutic activities are also described, as is the role of phytocannabinoid remodelling to accelerate therapeutic portfolio expansion in C. sativa.