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