Characterization and engineering of the biosynthesis of alternative painkilling natural products

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The plant kingdom remains a great source for complex and bioactive specialized metabolites for medicine. Flowering plants provide 11% of the essential medicines listed by the World Health Organization. For millions of years, these specialized metabolites have been evolving while they participate in plant-plant/microbe/animal communications and plant defense against various attacks. This evolution has resulted in their great structural diversity responsible for their diverse bioactivities. It is of great interest to study their biochemical assembly to understand the origin of such chemo-diversity and to provide solutions to access the rare bioactive compounds by emerging synthetic biology. As the NBHRF/Tetra Bio-Pharma Cannabis Health Research Chair at University of New Brunswick, I study the biochemistry and molecular regulations of the production of specialized metabolites, cannabinoids, in the cannabis plant. My cannabis research program is integral to my long-term objectives: i) to understand how the evolution of enzyme catalysts from different plant species contributes to Nature's chemo-diversity by elucidating the biochemical pathways involved, and ii) to identify and harness these enzymes for manufacturing important natural products. Support from NSERC will contribute to achieving this ambition. During the grant period, I will focus on the characterization and engineering of the biosynthesis of alternative painkilling natural products that may replace effective but problematic opioids. Short-term objectives include elucidating the complete biosynthesis of 1) conolidine, and 2) perrottetinene, and 3) engineering their microbial production for industrial manufacturing. Operating in a mode different from opioids, conolidine is a potent but non-addictive analgesic. Its extremely low content in source plants and the challenges remaining in chemical synthesis, however, impede its development as a medicine. Studying the biosynthesis of conolidine also contributes to understanding the chemical evolution of an important metabolite class: monoterpenoid indole alkaloids, which have impressive structural complexity and diversity that gives them fascinating bioactivities. Isolated from Radula spp. in the phylum of liverwort, perrottetinene shows astonishing structural similarity to tetrahydrocannabinol (THC) from the vascular plant Cannabis sativa, which was known as the only species for cannabinoids and diverged from liverworts 480 million years ago. As a human cannabinoid receptor ligand, perrottetinene may be developed into a promising analgesic, since the endocannabinoid system has become a target in pain management. By comparing this substance to the biosynthesis of THC, we aim to answer how these structurally similar compounds have evolved in two distantly related species, and also develop new enzyme catalysts for producing cannabinoid analgesics.