Discovery of a widely distributed toxin biosynthetic gene cluster

Shaun W. Lee, Douglas A. Mitchell, Andrew L. Markley, Mary E. Hensler, David Gonzalez, Aaron Wohlrab, Pieter C. Dorrestein, Victor Nizet, Jack E. Dixon

Research output: Contribution to journalArticlepeer-review

Abstract

Bacteriocins represent a large family of ribosomally produced peptide antibiotics. Here we describe the discovery of a widely conserved biosynthetic gene cluster for the synthesis of thiazole and oxazole heterocycles on ribosomally produced peptides. These clusters encode a toxin precursor and all necessary proteins for toxin maturation and export. Using the toxin precursor peptide and heterocycle-forming synthetase proteins from the human pathogen Streptococcus pyogenes, we demonstrate the in vitro reconstitution of streptolysin S activity. We provide evidence that the synthetase enzymes, as predicted from our bioinformatics analysis, introduce heterocycles onto precursor peptides, thereby providing molecular insight into the chemical structure of streptolysin S. Furthermore, our studies reveal that the synthetase exhibits relaxed substrate specificity and modifies toxin precursors from both related and distant species. Given our findings, it is likely that the discovery of similar peptidic toxins will rapidly expand to existing and emerging genomes.

Original languageEnglish (US)
Pages (from-to)5879-5884
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number15
DOIs
StatePublished - Apr 15 2008
Externally publishedYes

Keywords

  • Antibiotics
  • Bacteriocin
  • Bioinformatics
  • Hemolytic
  • Streptolysin

ASJC Scopus subject areas

  • General

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