Escherichia coli-Derived γ-Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis

Org Lett. 2021 Sep 3;23(17):6895-6899. doi: 10.1021/acs.orglett.1c02461. Epub 2021 Aug 18.

Abstract

Colibactin is a genotoxic hybrid polyketide-nonribosomal peptide that drives colorectal cancer initiation. While clinical data suggest colibactin genotoxicity in vivo is largely caused by the major DNA-cross-linking metabolite, the colibactin locus produces a diverse collection of metabolites with mostly unknown biological activities. Here, we describe 10 new colibactin pathway metabolites (1-10) that are dependent on its α-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated and structurally characterized mainly by nuclear magnetic resonance spectroscopy to be γ-lactam derivatives, and the remaining related structures were inferred via shared biosynthetic logic. Our proposed formation of 1-10, which is supported by stereochemical analysis, invokes cross-talk between colibactin and fatty acid biosynthesis, illuminating further the complexity of this diversity-oriented pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage
  • Escherichia coli / chemistry*
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / genetics
  • Fatty Acids / chemistry*
  • Fatty Acids / metabolism
  • Humans
  • Lactams / chemistry
  • Lactams / metabolism
  • Molecular Structure
  • Peptides / chemistry*
  • Polyketides / chemistry*

Substances

  • Escherichia coli Proteins
  • Fatty Acids
  • Lactams
  • Peptides
  • Polyketides
  • colibactin