Free radical mediated C-C bond formation in cofactor and natural product biosynthesis

Seminar | April 4 | 11 a.m.-12 p.m. |  Pitzer Auditorium, 120 Latimer Hall

 Dr. Kenichi Yokoyama, Department of Biochemistry, Duke University

 College of Chemistry

My group has been studying the functions and mechanisms of enzymes that catalyze key steps in backbone construction of natural products and cofactors. In particular, we are interested in how free radicals are being used in C-C bond formation. In this seminar, I will focus on our recent work on biosynthesis of antifungal peptidylnucleoside (PN) natural products represented by nikkomycins and polyoxins. The nucleoside moiety (aminohexuronic acid, AHA) of PNs is the pharmacophore essential for the antifungal activity, and is biosynthesized via a C5′-extended bicyclic high-carbon nucleoside. Our studies revealed that this C5’-extension proceeds by a unique mechanism by a novel radical S-adenosyl-L-methionine (SAM) enzyme, PolH. PolH was identified based on the functional characterization of enzymes conserved between the nikkomycin and polyoxin biosynthetic gene clusters, and found to catalyze the conversion of enolpyruvyl uridine 5′-monophosphate (EP-UMP) into octosyl acid 5′-phosphate (OAP) by a free radical-mediated C-C bond formation using the redox active C209 residue to stereospecifically reduce a free radical intermediate. This mechanism is distinct from the nucleophilic mechanism known for C5′-extension in antibacterial nucleoside biosynthesis, and hence represents a novel mechanism of nucleoside natural product biosynthesis. Further bioinformatic analysis revealed homologs of PolH, and potentials for genome-mining discovery of OAP-related antifungal natural products.
Lilla, E. A.; Yokoyama, K., Nature Chemical Biology 2016, 12(11):905-907., 510-643-0572