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One-Pot Enzymatic Synthesis of Merochlorin A and B

Authors


  • We thank Peter Bernhardt, Brendan Duggan, and Stefanie Maerten for technical assistance. This research was supported by the US National Institute of Health (NIH, Grant No. R01-AI047818) and by postdoctoral fellowships to R.T. from the Deutsche Forschungsgemeinschaft (TE 931/1-1), to L.K. from the Alexander von Humboldt Foundation, and to S.D. from the Swiss National Science Foundation (SNF).

Abstract

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH-189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide-terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium-dependent haloperoxidase, thus completing the remarkably efficient pathway.

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