Formicamycin biosynthesis involves a unique reductive ring contraction

Zhiwei Qin, Rebecca Devine, Thomas J. Booth, Elliot H. E. Farrar, Matthew N. Grayson, Matthew I. Hutchings, Barrie Wilkinson

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Abstract

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.
Original languageEnglish
Pages (from-to)8125-8131
Number of pages7
JournalChemical Science
Volume11
Issue number31
Early online date16 Jun 2020
DOIs
Publication statusPublished - 21 Aug 2020

ASJC Scopus subject areas

  • Chemistry(all)

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