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Anti-Inflammatory α-Pyrone Polyethers Generated by Interrupting the Enolized 1,3-Diketone Formation in the Polyketide
Mengjia Li1, Jing Xu1, Haixia Zang1
1Research Center for Marine Drugs, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Abstract:
Carboxyl polyethers from Actinomycetes have diverse bioactivities, being biosynthesized by type-I polyketide synthetases. Of them, ionomycin, the commercial calcium ionophore, bears a unique enolized 1,3-diketone moiety. Herein, mutagenetic analysis of ionomycin biosynthesis revealed a rare dehydrogenase gene inoJ putatively involved in enol moiety formation. Interruption of the enolized 1,3-diketone formation by inactivating a ketoreductase domain yielded the first natural polyether with an α-pyrone ring, which was demonstrated with significant anti-inflammatory activity in a mouse colitis model.
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