title: Discovery of a widely distributed toxin biosynthetic gene cluster.
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.
authors: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Shaun W
authors: SW
authors: Lee
authors: Douglas A
authors: DA
authors: Mitchell
authors: Andrew L
authors: AL
authors: Markley
authors: Mary E
authors: ME
authors: Hensler
authors: David
authors: D
authors: Gonzalez
authors: Aaron
authors: A
authors: Wohlrab
authors: Pieter C
authors: PC
authors: Dorrestein
authors: Victor
authors: V
authors: Nizet
authors: Jack E
authors: JE
authors: Dixon
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000378:metabolism; D001430:Bacteriocins / Q000096:biosynthesis*; D006571:Heterocyclic Compounds; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D005810:Multigene Family; D010080:Oxazoles; D013297:Streptococcus pyogenes / Q000201:enzymology*; D013301:Streptolysins / Q000378:metabolism; D013844:Thiazoles
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001430:Bacteriocins; D006571:Heterocyclic Compounds; D009097:Multienzyme Complexes; D010080:Oxazoles; D013301:Streptolysins; D013844:Thiazoles; C026050:streptolysin S