Cytochrome P450-mediated hydroxylation is required for polyketide macrolactonization in stambomycin biosynthesis

Lijiang Song, Luisa Laureti, Christophe Corre, Pierre Leblond, Bertrand Aigle, Gregory L. Challis

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

Abstract

Many polyketide antibiotics contain macrolactones that arise from polyketide synthase chain release via thioesterase (TE) domain-catalyzed macrolactonization. The hydroxyl groups utilized in such macrolactonization reactions typically derive from reduction of β-ketothioester intermediates in polyketide chain assembly. The stambomycins are a group of novel macrolide antibiotics with promising anticancer activity that we recently discovered via rational activation of a silent polyketide biosynthetic gene cluster in Streptomyces ambofaciens. Here we report that the hydroxyl group utilized for formation of the macrolactone in the stambomycins is derived from cytochrome P450-catalyzed hydroxylation of the polyketide chain rather than keto reduction during chain assembly. This is a novel mechanism for macrolactone formation in polyketide antibiotic biosynthesis.

Original languageEnglish
Pages (from-to)71-76
Number of pages6
JournalJournal of Antibiotics
Volume67
Issue number1
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Acyl carrier protein
  • Cytochrome P450
  • Hydroxylation
  • Macrolactonization
  • Polyketide synthase
  • Streptomyces ambofaciens
  • Thioesterase

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