Formicamycin biosynthesis involves a unique reductive ring contraction

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 occursviaa novel two-step ring expansion-ring contraction pathway. Deletion offorX, encoding a flavin dependent monooxygenase, abolished formicamycin production and leads to accumulation of fasamycin E. Deletion of the adjacent geneforY, 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. Throughin vivocross 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
DOIs
Publication statusPublished - 21 Aug 2020
Externally publishedYes

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