Microbial Synthesis of Plant Alkaloids

Of the roughly 12,000 alkaloids naturally produced by plant species, roughly half comprise the monoterpene indole alkaloid (MIA) and benzylisoquinoline alkaloid (BIA) families. These compounds include the opiate analgesics morphine and codeine, the anticancer agents vinblastine and vincristine, and a vast assemblage of other untapped pharmacological activities. Low in planta metabolite levels, a lack of robust genetic tools for plant metabolic engineering, and complex product stereochemistry render both crop-based manufacturing and total chemical synthesis unfeasible for the majority of plant alkaloids. Instead, recent achievements in enzyme discovery and pathway elucidation coupled with the advent of synthetic biology have provided a framework for assembling plant alkaloid pathways in tractable microorganisms. In this chapter we provide an overview of MIA and BIA biosynthetic networks and highlight key pathway and biochemical commonalities shared by these two metabolite classes. In light of the recent intense period of pathway elucidation and reconstitution, we recapitulate efforts to assemble MIA and BIA branches in Escherichia coli and yeast (Saccharomyces cerevisiae). Finally, we survey genetic strategies and fermentation conditions that will play pivotal roles in boosting microbial alkaloid production to industrially relevant titers.