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Structural basis for backbone N-methylation by an interrupted adenylation domain

Abstract

Interrupted adenylation domains are enigmatic fusions, in which one enzyme is inserted into another to form a highly unusual bifunctional enzyme. We present the first crystal structure of an interrupted adenylation domain that reveals a unique embedded methyltransferase. The structure and functional data provide insight into how these enzymes N-methylate amino acid precursors en route to nonribosomal peptides.

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Fig. 1: Structure of TioS(A4aM4A4b).
Fig. 2: Catalytic activities of the A and the M domain of TioS(A4aM4A4b).

References

  1. 1.

    Park, H. B. et al. J. Nat. Prod. 74, 2309–2312 (2011).

    CAS  Article  Google Scholar 

  2. 2.

    Chatterjee, J., Rechenmacher, F. & Kessler, H. Angew. Chem. Int. Ed. Engl. 52, 254–269 (2013).

    CAS  Article  Google Scholar 

  3. 3.

    Chatterjee, J., Gilon, C., Hoffman, A. & Kessler, H. Acc. Chem. Res. 41, 1331–1342 (2008).

    CAS  Article  Google Scholar 

  4. 4.

    van der Velden, N.S. et al. Nat. Chem. Biol. 13, 833–835 (2017).

  5. 5.

    Ramm, S. et al. Angew. Chem. Int. Ed. Engl. 56, 9994–9997 (2017).

  6. 6.

    Labby, K. J., Watsula, S. G. & Garneau-Tsodikova, S. Nat. Prod. Rep. 32, 641–653 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Lombo, F. et al. ChemBioChem 7, 366–376 (2006).

    CAS  Article  Google Scholar 

  8. 8.

    Watanabe, K. et al. Nat. Chem. Biol. 2, 423–428 (2006).

    CAS  Article  Google Scholar 

  9. 9.

    Praseuth, A. P. et al. Biotechnol. Prog. 24, 1226–1231 (2008).

    CAS  Article  Google Scholar 

  10. 10.

    Watanabe, K. et al. J. Am. Chem. Soc. 131, 9347–9353 (2009).

    CAS  Article  Google Scholar 

  11. 11.

    Reimer, J. M., Aloise, M. N., Harrison, P. M. & Schmeing, T. M. Nature 529, 239–242 (2016).

    CAS  Article  Google Scholar 

  12. 12.

    Zhang, W., Heemstra, J. R. Jr., Walsh, C. T. & Imker, H. J. Biochemistry 49, 9946–9947 (2010).

    CAS  Article  Google Scholar 

  13. 13.

    Felnagle, E. A. et al. Biochemistry 49, 8815–8817 (2010).

    CAS  Article  Google Scholar 

  14. 14.

    Herbst, D. A., Boll, B., Zocher, G., Stehle, T. & Heide, L. J. Biol. Chem. 288, 1991–2003 (2013).

    CAS  Article  Google Scholar 

  15. 15.

    Miller, B. R., Drake, E. J., Shi, C., Aldrich, C. C. & Gulick, A. M. J. Biol. Chem. 291, 22559–22571 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Tarry, M. J., Haque, A. S., Bui, K. H. & Schmeing, T. M. Structure 25, 783–793 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Shi, R. et al. PLoS Biol. 8, e1000354 (2010).

    Article  Google Scholar 

  18. 18.

    Al-Mestarihi, A. H. et al. J. Am. Chem. Soc. 136, 17350–17354 (2014).

    CAS  Article  Google Scholar 

  19. 19.

    Mori, S., Garzan, A., Tsodikov, O. V. & Garneau-Tsodikova, S. Biochemistry 56, 6087–6097 (2017).

    CAS  Article  Google Scholar 

  20. 20.

    Ansari, M. Z., Sharma, J., Gokhale, R. S. & Mohanty, D. BMC Bioinformatics 9, 454 (2008).

    Article  Google Scholar 

  21. 21.

    Nakaya, M. et al. Biosci. Biotechnol. Biochem. 71, 2969–2976 (2007).

    CAS  Article  Google Scholar 

  22. 22.

    Hercouet, A., Bessieres, B. & Le Corre, M. Tetrahedron 7, 283–284 (1996).

    CAS  Article  Google Scholar 

  23. 23.

    Zolova, O. E. & Garneau-Tsodikova, S. Med. Chem. Commun. 3, 950–955 (2012).

    CAS  Article  Google Scholar 

  24. 24.

    Mady, A. S. et al. Mol. BioSyst. 7, 1999–2011 (2011).

    CAS  Article  Google Scholar 

  25. 25.

    Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).

    CAS  Article  Google Scholar 

  26. 26.

    McCoy, A. J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  Article  Google Scholar 

  27. 27.

    Murshudov, G. N. et al. Acta Crystallogr. D Biol. Crystallogr. 67, 355–367 (2011).

    CAS  Article  Google Scholar 

  28. 28.

    Emsley, P. & Cowtan, K. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a NSF CAREER Award MCB-1149427 (to S.G.-T.) and by startup funds from the College of Pharmacy at the University of Kentucky (to S.G.-T. and O.V.T.).

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S.M., A.H.P., T.A.L., O.V.T., and S.G.-T. designed the study and wrote the manuscript. S.M. and T.A.L. performed biochemical experiments. A.H.P. performed crystallization and structure determination. A.G. performed chemical synthesis. S.M. and A.H.P. contributed equally.

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Correspondence to Oleg V. Tsodikov or Sylvie Garneau-Tsodikova.

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Supplementary Tables 1–4 and Supplementary Figure 1–21

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Mori, S., Pang, A.H., Lundy, T.A. et al. Structural basis for backbone N-methylation by an interrupted adenylation domain. Nat Chem Biol 14, 428–430 (2018). https://doi.org/10.1038/s41589-018-0014-7

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