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Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes

Abstract

Methylation is among the most widespread chemical modifications encountered in biomolecules and has a pivotal role in many major biological processes. In the biosynthetic pathway of the antibiotic thiostrepton A, we identified what is to our knowledge the first tryptophan methyltransferase. We show that it uses unprecedented chemistry to methylate inactivated sp2-hybridized carbon atoms, despite being predicted to be a radical SAM enzyme.

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Figure 1: Biosynthesis of thiostrepton A.
Figure 2: Analysis of the products formed by TsrM during reaction.
Figure 3: Activity and proposed mechanism for TsrM.

References

  1. Walsh, C.T., Acker, M.G. & Bowers, A.A. J. Biol. Chem. 285, 27525–27531 (2010).

    Article  CAS  Google Scholar 

  2. Nicolaou, K.C. et al. J. Am. Chem. Soc. 127, 15042–15044 (2005).

    Article  CAS  Google Scholar 

  3. Tarr, S.J., Nisbet, R.E. & Howe, C.J. Mol. Biochem. Parasitol. 179, 37–41 (2011).

    Article  CAS  Google Scholar 

  4. Hegde, N.S., Sanders, D.A., Rodriguez, R. & Balasubramanian, S. Nat. Chem. 3, 725–731 (2011).

    Article  CAS  Google Scholar 

  5. Kwok, J.M. et al. Mol. Cancer Res. 8, 24–34 (2010).

    Article  CAS  Google Scholar 

  6. Kelly, W.L., Pan, L. & Li, C. J. Am. Chem. Soc. 131, 4327–4334 (2009).

    Article  CAS  Google Scholar 

  7. Zhou, P. et al. J. Am. Chem. Soc. 111, 7274–7276 (1989).

    Article  CAS  Google Scholar 

  8. Frenzel, T., Zhou, P. & Floss, H.G. Arch. Biochem. Biophys. 278, 35–40 (1990).

    Article  CAS  Google Scholar 

  9. Frey, P.A., Hegeman, A.D. & Ruzicka, F.J. Crit. Rev. Biochem. Mol. Biol. 43, 63–88 (2008).

    Article  CAS  Google Scholar 

  10. Grove, T.L. et al. Science 332, 604–607 (2011).

    Article  CAS  Google Scholar 

  11. Benjdia, A. et al. J. Biol. Chem. 283, 17815–17826 (2008).

    Article  CAS  Google Scholar 

  12. Benjdia, A. et al. FEBS J. 277, 1906–1920 (2010).

    Article  CAS  Google Scholar 

  13. Benjdia, A., Leprince, J., Sandstrom, C., Vaudry, H. & Berteau, O. J. Am. Chem. Soc. 131, 8348–8349 (2009).

    Article  CAS  Google Scholar 

  14. Werner, W.J. et al. Biochemistry 50, 8986–8988 (2011).

    Article  CAS  Google Scholar 

  15. Yan, F. et al. J. Am. Chem. Soc. 132, 3953–3964 (2010).

    Article  CAS  Google Scholar 

  16. Matthews, R.G., Koutmos, M. & Datta, S. Curr. Opin. Struct. Biol. 18, 658–666 (2008).

    Article  CAS  Google Scholar 

  17. Zhang, Q., van der Donk, W.A. & Liu, W. Acc. Chem. Res. 45, 555–564 (2012).

    Article  Google Scholar 

  18. Moore, B.N. & Julian, R.R. Phys. Chem. Chem. Phys. 14, 3148–3154 (2012).

    Article  CAS  Google Scholar 

  19. Mosimann, H. & Krautler, B. Angew. Chem. Int. Edn Engl. 39, 393–395 (2000).

    Article  CAS  Google Scholar 

  20. Menon, S. & Ragsdale, S.W. Biochemistry 37, 5689–5698 (1998).

    Article  CAS  Google Scholar 

  21. Houck, D.R., Kobayashi, K., Williamson, J.M. & Floss, H.G. J. Am. Chem. Soc. 108, 5365–5366 (1986).

    Article  CAS  Google Scholar 

  22. Gloux, K. et al. Proc. Natl. Acad. Sci. USA 108 (suppl. 1), 4539–4546 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to J. Ulmer for critical reading of this manuscript. MS experiments were performed at Plateforme d'Analyse Protéomique de Paris Sud-Ouest. This work was supported by grants from the French National Research Agency to S.P.

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Contributions

The research was conceived by S.P., A.B. and O.B. S.P., A.B., A.G., C.S. and O.B. performed experiments. S.P., A.B., A.G., P.L. and O.B. analyzed the data. S.P., A.B. and O.B. wrote the manuscript.

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Correspondence to Olivier Berteau.

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The authors declare no competing financial interests.

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Pierre, S., Guillot, A., Benjdia, A. et al. Thiostrepton tryptophan methyltransferase expands the chemistry of radical SAM enzymes. Nat Chem Biol 8, 957–959 (2012). https://doi.org/10.1038/nchembio.1091

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