One-Pot Enzymatic Synthesis of Merochlorin A and B

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. Assembly line: The biosynthetic pathway to merochlorins A and B was fully reconstituted in vitro and involves only four enzymes. The assembly route starts from the common metabolites dimethylallyl diphosphate, geranyl diphosphate, and malonyl CoA, which are transformed into an unusual polyketide‐terpene hybrid intermediate. Oxidative chlorination and terpene cyclization complete the remarkably short pathway to the merochlorins.