Angew. Chem. Int. Ed. 10.1002/anie.201405694

Angew. Chem. Int. Ed. 10.1002/anie.201405696

Merochlorins A and B are natural products that contain complex ring structures and carbon–chlorine bonds. Teufel et al. now report the reconstitution of the merochlorin biosynthetic pathway in vitro, which generates these two terpenoids from dimethylallyl diphosphate (DMAPP), geranyldiphosphate (GPP) and malonyl–CoA. The authors first showed that Mcl17, which is homologous to type III polyketide synthases, could produce the tetrahydroxynapthalene ring from five molecules of malonyl–CoA. They then determined that Mcl22 joined GPP and DMAPP via a highly unusual 'head-to-torso' coupling reaction, thereby forming a branched sesquiterpene diphosphate. Mcl23 was shown to mediate the coupling of this sesquiterpene diphosphate to the tetrahydroxynaphthalene ring in vitro. As the authors were not able to generate sufficient pre-merochlorin via enzymatic synthesis to carry out additional experiments, they chemically synthesized this molecule. Addition of this compound to a Δmcl23 strain of Streptomyces led to the production of both merochlorins, indicating that pre-merochlorin was an intermediate in the biosynthetic pathway. In a companion paper, Diethelm et al. showed that the vanadium-dependent haloperoxidase Mcl24 catalyzed the site-specific chlorination of the naphthalene ring and the subsequent oxidative dearomatization-cyclization reaction cascade to ultimately generate merochlorins A and B. These results provide a compelling example of how architecturally complex natural products can be generated from three simple building blocks using just four enzymes.