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Abstract
Monoterpene indole alkaloids (MIAs) have important therapeutic value, including as anticancer and antimalarial agents. Because of their chemical complexity, therapeutic MIAs, or advanced intermediates thereof, are often isolated from the native plants. The microbial synthesis of MIAs would allow for the rapid and scalable production of complex MIAs and MIA analogues for therapeutic use. Here, we produce the modified MIA hydroxystrictosidine from glucose and the monoterpene secologanin via a pterin-dependent mono-oxidation strategy. Specifically, we engineered the yeast Saccharomyces cerevisiae for the high-level synthesis of tetrahydrobiopterin to mono-oxidize tryptophan to 5-hydroxytryptophan, which, after decarboxylation to serotonin, is coupled to exogenously fed secologanin to produce 10-hydroxystrictosidine in an eight-enzyme pathway. We selected hydroxystrictosidine as our synthetic target because hydroxylation at the 10' position of the alkaloid core strictosidine provides a chemical handle for the future chemical semisynthesis of therapeutics. We show the generality of the pterin-dependent mono-oxidation strategy for alkaloid synthesis by hydroxylating tyrosine to L-DOPA-a key intermediate in benzylisoquinoline alkaloid (BIA) biosynthesis-and, thereafter, further converting it to dopamine. Together, these results present the first microbial synthesis of a modified alkaloid, the first production of tetrahydrobiopterin in yeast, and the first use of a pterin-dependent mono-oxidation strategy for the synthesis of L-DOPA. This work opens the door to the scalable production of MIAs as well as the production of modified MIAs to serve as late intermediates in the semisynthesis of known and novel therapeutics. Further, the microbial strains in this work can be used as plant pathway discovery tools to elucidate known MIA biosynthetic pathways or to identify pathways leading to novel MIAs.
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