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§,¶, and
- Jack E. Dixon*,†,‡,‖,**
- *Department of Pharmacology,
- †Department of Cellular and Molecular Medicine,
- ‡Department of Chemistry and Biochemistry,
- §Skaggs School of Pharmacy and Pharmaceutical Sciences, and
- ¶Department of Pediatricas, Division of Pharmacology and Drug Discovery, University of California at San Diego, La Jolla, CA 92093; and
- ‖Howard Hughes Medical Institute, Chevy Chase, MD 20815
-
Contributed by Jack E. Dixon, February 10, 2008 (received for review February 5, 2008)
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.
Footnotes
- **To whom correspondence should be addressed at: Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789. E-mail: jedixon{at}ucsd.edu
-
Author contributions: S.W.L. and D.A.M. contributed equally to this work; S.W.L., D.A.M., M.E.H., P.C.D., and J.E.D. designed research; S.W.L., D.A.M., A.L.M., M.E.H., D.G., A.W., and P.C.D. performed research; S.W.L., D.A.M., A.L.M., and M.E.H. contributed new reagents/analytic tools; S.W.L., D.A.M., A.L.M., M.E.H., D.G., A.W., P.C.D., V.N., and J.E.D. analyzed data; and S.W.L., D.A.M., and J.E.D. wrote the paper.
-
The authors declare no conflict of interest.
-
See Commentary on page 5655.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0801338105/DCSupplemental.
- © 2008 by The National Academy of Sciences of the USA
