Abstract
The enterococcal cytolysin is a two-component lantibiotic of unknown structure with hemolytic activity that is important for virulence. We prepared cytolysin by coexpression of each precursor peptide with the synthetase CylM in Escherichia coli and characterized its structure. Unexpectedly, cytolysin is to our knowledge the first example of a lantibiotic containing lanthionine and methyllanthionine structures with different stereochemistries in the same peptide. The stereochemistry is determined by the sequence of the substrate peptide.
Similar content being viewed by others
References
Gilmore, M.S. et al. J. Bacteriol. 176, 7335–7344 (1994).
Cox, C.R., Coburn, P.S. & Gilmore, M.S. Curr. Protein Pept. Sci. 6, 77–84 (2005).
Lawton, E.M., Ross, R.P., Hill, C. & Cotter, P.D. Mini Rev. Med. Chem. 7, 1236–1247 (2007).
Bierbaum, G. & Sahl, H.G. Curr. Pharm. Biotechnol. 10, 2–18 (2009).
Ike, Y. & Clewell, D.B. J. Bacteriol. 158, 777–783 (1984).
Chow, J.W. et al. Antimicrob. Agents Chemother. 37, 2474–2477 (1993).
Huycke, M.M., Spiegel, C.A. & Gilmore, M.S. Antimicrob. Agents Chemother. 35, 1626–1634 (1991).
Coburn, P.S. & Gilmore, M.S. Cell. Microbiol. 5, 661–669 (2003).
Haas, W., Shepard, B.D. & Gilmore, M.S. Nature 415, 84–87 (2002).
Coburn, P.S., Pillar, C.M., Jett, B.D., Haas, W. & Gilmore, M.S. Science 306, 2270–2272 (2004).
Knerr, P.J. & van der Donk, W.A. Annu. Rev. Biochem. 81, 479–505 (2012).
Haas, W. & Gilmore, M.S. Med. Microbiol. Immunol. (Berl.) 187, 183–190 (1999).
Gilmore, M.S., Segarra, R.A. & Booth, M.C. Infect. Immun. 58, 3914–3923 (1990).
Segarra, R.A., Booth, M.C., Morales, D.A., Huycke, M.M. & Gilmore, M.S. Infect. Immun. 59, 1239–1246 (1991).
Booth, M.C. et al. Mol. Microbiol. 21, 1175–1184 (1996).
Shi, Y., Yang, X., Garg, N. & van der Donk, W.A. J. Am. Chem. Soc. 133, 2338–2341 (2011).
McClerren, A.L. et al. Proc. Natl. Acad. Sci. USA 103, 17243–17248 (2006).
Chatterjee, C., Paul, M., Xie, L. & van der Donk, W.A. Chem. Rev. 105, 633–684 (2005).
Liu, W., Chan, A.S.H., Liu, H.Q., Cochrane, S.A. & Vederas, J.C. J. Am. Chem. Soc. 133, 14216–14219 (2011).
Tang, W. & van der Donk, W.A. Biochemistry 51, 4271–4279 (2012).
Hyink, O., Balakrishnan, M. & Tagg, J.R. FEMS Microbiol. Lett. 252, 235–241 (2005).
Yonezawa, H. & Kuramitsu, H.K. Antimicrob. Agents Chemother. 49, 541–548 (2005).
Garg, N., Tang, W.X., Goto, Y., Nair, S.K. & van der Donk, W.A. Proc. Natl. Acad. Sci. USA 109, 5241–5246 (2012).
Ike, Y., Clewell, D.B., Segarra, R.A. & Gilmore, M.S. J. Bacteriol. 172, 155–163 (1990).
Ross, A.C. & Vederas, J.C. J. Antibiot. (Tokyo) 64, 27–34 (2011).
Li, B., Cooper, L.E. & van der Donk, W.A. Methods Enzymol. 458, 533–558 (2009).
Cooper, L.E., McClerren, A.L., Chary, A. & van der Donk, W.A. Chem. Biol. 15, 1035–1045 (2008).
Oman, T.J. & van der Donk, W.A. ACS Chem. Biol. 4, 865–874 (2009).
Acknowledgements
We thank X. Yang (University of Illinois) for providing the modified HalA2 and Halβ peptides. This work was supported by the US National Institutes of Health (GM58822).
Author information
Authors and Affiliations
Contributions
W.T. and W.A.v.d.D. designed the study. W.T. performed all experiments. W.T. and W.A.v.d.D. analyzed the data and wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Results (PDF 2167 kb)
Rights and permissions
About this article
Cite this article
Tang, W., van der Donk, W. The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry. Nat Chem Biol 9, 157–159 (2013). https://doi.org/10.1038/nchembio.1162
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchembio.1162
- Springer Nature America, Inc.
This article is cited by
-
Conformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis
Nature Communications (2021)
-
CylA is a sequence-specific protease involved in toxin biosynthesis
Journal of Industrial Microbiology and Biotechnology (2019)
-
Lanthipeptides: chemical synthesis versus in vivo biosynthesis as tools for pharmaceutical production
Microbial Cell Factories (2016)
-
Substrate control in stereoselective lanthionine biosynthesis
Nature Chemistry (2015)
-
The road to L
Nature Chemistry (2015)