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Formicamycin biosynthesis involves a unique reductive ring contraction† †Electronic supplementary information (ESI) available: General remarks; full experimental details; Fig. S1–S60 and Tables S1–S5. See DOI: 10.1039/d0sc01712d

ABSTRACT: Using a combination of biomimetic chemistry and molecular genetics we demonstrate that formicamycin biosynthesis proceeds via reductive Favorskii-like reaction. Fasamycin natural products are biosynthetic precursors of the formicamycins. Both groups of compounds are polyketide natural products that exhibit potent antibacterial activity despite displaying different three-dimensional topologies. We show here that transformation of fasamycin into formicamycin metabolites requires two gene products and occurs via a novel two-step ring expansion-ring contraction pathway. Deletion of forX, encoding a flavin dependent monooxygenase, abolished formicamycin production and leads to accumulation of fasamycin E. Deletion of the adjacent gene forY, encoding a flavin dependent oxidoreductase, also abolished formicamycin biosynthesis and led to the accumulation of new lactone metabolites that represent Baeyer–Villiger oxidation products of the fasamycins. These results identify ForX as a Baeyer–Villiger monooxygenase capable of dearomatizing ring C of the fasamycins. Through in vivo cross feeding and biomimetic semi-synthesis experiments we showed that these lactone products represent biosynthetic intermediates that are reduced to formicamycins in a unique reductive ring contraction reaction catalyzed by ForY.

SUBMITTER: Qin Z

PROVIDER: S-EPMC7504897 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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