Phytocannabinoids: Origins and Biosynthesis

Phytocannabinoids are bioactive natural products found in some flowering plants, liverworts, and fungi that can be beneficial for the treatment of human ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabinoids with desirable properties requires identification of the underlying genes and their expression in a suitable heterologous host. We provide an overview of the structural classification of phytocannabinoids based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Rhododendron, and Radula species. We also highlight the potential in planta roles of phytocannabinoids and the opportunity for synthetic biology approaches based on combinatorial biochemistry and protein engineering to produce cannabinoid derivatives with improved properties. Phytocannabinoids are bioactive terpenoids that were thought to be exclusive to Cannabis sativa, but have now also been discovered in Rhododendron species, some legumes, the liverwort genus Radula, and some fungi.Many cannabinoids display promising non-hallucinogenic bioactivities that are determined by the variable nature of the side chain and prenyl group defined by the enzymes involved in their synthesis.The biosynthesis of cannabinoids in C. sativa is fully elucidated, whereas the pathways in Rhododendron and Radula have only recently gained research attention.Cannabinoid biosynthesis is highly modular, enabling use of the modules identified in synthetic biology-based combinatorial approaches, as demonstrated by the generation of new-to-nature cannabinoids in Saccharomyces cerevisiae.The ecological functions of cannabinoids include protection against UV light and desiccation, as well as in plant defense.