Monoterpene indole alkaloids (MIAs) have important therapeutic value, including as anticancer and antimalarial agents. Due to their chemical complexity, therapeutic MIAs, or advanced intermediates thereof, are often isolated from the native plants and chemically derivatized. The microbial synthesis of modified MIAs carrying chemical handles at key positions would accelerate the semi-synthesis of known therapeutic MIAs or novel MIA analogs with potential therapeutic activity. Here, I will present our recent work on the microbial synthesis of the modified MIA 10-hydroxystrictosidine from glucose and the monoterpene secologanin via a pterin-dependent mono-oxidation strategy. Hydroxylation at the 10’ position of strictosidine, will accelerate the semi-synthesis of anticancer therapeutics modified at that key position. Our work will open the door to the scalable production of modified MIAs to serve as late intermediates in the semi-synthesis of known and novel therapeutics. Further, our microbial strains can be used as plant pathway discovery tools to elucidate known MIA biosynthetic pathways or to identify pathways leading to novel MIAs, which we are starting to explore.

Microbial synthesis of modified alkaloids for the generation of known and novel therapeutics

251st National Meeting (2016)

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