Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates

Nature Structural Biology volume 9, pages 653–658 (2002)Cite this article

Abstract

AAC(2′)-Ic catalyzes the coenzyme A (CoA)-dependent acetylation of the 2′ hydroxyl or amino group of a broad spectrum of aminoglycosides. The crystal structure of the AAC(2′)-Ic from Mycobacterium tuberculosis has been determined in the apo enzyme form and in ternary complexes with CoA and either tobramycin, kanamycin A or ribostamycin, representing the first structures of an aminoglycoside acetyltransferase bound to a drug. The overall fold of AAC(2′)-Ic places it in the GCN5-related N-acetyltransferase (GNAT) superfamily. Although the physiological function of AAC(2′)-Ic is uncertain, a structural analysis of these high-affinity aminoglycoside complexes suggests that the enzyme may acetylate a key biosynthetic intermediate of mycothiol, the major reducing agent in mycobacteria, and participate in the regulation of cellular redox potential.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The chemical reaction and overall structure of AAC(2′)-Ic.
Figure 2: Interactions of the CoA and aminoglycosides with AAC(2′)-Ic.
Figure 3: Comparison of bound aminoglycosides and the chemical mechanism of acyltransfer by AAC(2′)-Ic.
Figure 4: Potential physiological function of AAC(2′)-Ic.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Shaw, K.J., Rather, P.N., Hare, R.S. & Miller, G.H. Microbiol. Rev. 57, 138–163 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Macinga, D.R. & Rather, P.N. Front. Biosci. 4, 132–140 (1999).

    Article  Google Scholar 

  3. Rather, P.N., Orosz, E., Shaw, K.J., Hare, R. & Miller, G. J. Bacteriol. 175, 6492–6498 (1993).

    Article  CAS  Google Scholar 

  4. Ainsa, J.A. et al. Mol. Microbiol. 24, 431–441 (1997).

    Article  CAS  Google Scholar 

  5. Hegde, S.S., Javid-Majd, F. & Blanchard, J.S. J. Biol. Chem. 276, 45876–45881 (2001).

    Article  CAS  Google Scholar 

  6. Dyda, F., Klein, D.C. & Hickman, A.B. Annu. Rev. Biophys. Biomol. Struct. 29, 81–103 (2000).

    Article  CAS  Google Scholar 

  7. Peneff, C., Mengin-Lecreulx, D. & Bourne, Y. J. Biol. Chem. 276, 16328–16334 (2001).

    Article  CAS  Google Scholar 

  8. Hickman, A.B., Klein, D.C. & Dyda, F. Mol. Cell 3, 23–32 (1999).

    Article  CAS  Google Scholar 

  9. Hickman, A.B., Namboodiri, M.A., Klein, D.C. & Dyda, F. Cell 97, 361–369 (1999).

    Article  CAS  Google Scholar 

  10. Dutnall, R.N., Tafrov, S.T., Sternglanz, R. & Ramakrishnan, V. Cell 94, 427–438 (1998).

    Article  CAS  Google Scholar 

  11. Angus-Hill, M.L., Dutnall, R.N., Tafrov, S.T., Sternglanz, R. & Ramakrishnan, V. J. Mol. Biol. 294, 1311–1325 (1999).

    Article  CAS  Google Scholar 

  12. Clements, A. et al. EMBO J. 18, 3521–3532 (1999).

    Article  CAS  Google Scholar 

  13. Trievel, R.C. et al. Proc. Natl. Acad. Sci. USA 96, 8931–8936 (1999).

    Article  CAS  Google Scholar 

  14. Lin, Y., Fletcher, C.M., Zhou, J., Allis, C.D. & Wagner, G. Nature 400, 86–89 (1999).

    Article  CAS  Google Scholar 

  15. Rojas, J.R. et al. Nature 401, 93–98 (1999).

    Article  CAS  Google Scholar 

  16. Yan, Y., Barlev, N.A., Haley, R.H., Berger, S.L. & Marmorstein, R. Mol. Cell 6, 1195–1205 (2000).

    Article  CAS  Google Scholar 

  17. Wybenga-Groot, L.E., Draker, K., Wright, G.D. & Berghuis, A.M. Struct. Fold. Des. 7, 497–507 (1999).

    Article  CAS  Google Scholar 

  18. Wolf, E. et al. Cell 94, 439–449 (1998).

    Article  CAS  Google Scholar 

  19. Kinoshita, K., Sadanami, K., Kidera, A. & Go, N. Protein Eng. 12, 11–14 (1999).

    Article  CAS  Google Scholar 

  20. Marmorstein, R. J. Mol. Biol. 311, 433–444 (2001).

    Article  CAS  Google Scholar 

  21. Bhatnagar, R.S., Futterer, K., Waksman, G. & Gordon, J.I. Biochim. Biophys. Acta 1441, 162–172 (1999).

    Article  CAS  Google Scholar 

  22. Payie, K.G. & Clarke, A.J. J. Bacteriol. 179, 4106–4114 (1997).

    Article  CAS  Google Scholar 

  23. Newton, G.L. et al. J. Bacteriol. 178, 1990–1995 (1996).

    Article  CAS  Google Scholar 

  24. Macinga, D.R., Cook, G.M., Poole, R.K. & Rather, P.N. J. Bacteriol. 180, 128–135 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Macinga, D.R., Paradise, M.R., Parojcic, M.M. & Rather, P.N. Antimicrob. Agents Chemother. 43, 1769–1772 (1999).

    Article  CAS  Google Scholar 

  26. Newton, G.L., Av-Gay, Y. & Fahey, R.C. J. Bacteriol. 182, 6958–6963 (2000).

    Article  CAS  Google Scholar 

  27. Anderberg, S.J., Newton, G.L. & Fahey, R.C. J. Biol. Chem. 273, 30391–30397 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Levitt, D.G. Acta Crystallogr. D 57, 1013–1019 (2001).

    Article  CAS  Google Scholar 

  30. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  31. Brünger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

  32. Navaza, J. Acta Crystallogr. A 50, 157–163 (1994).

    Article  Google Scholar 

  33. Kraulis, P.J. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

  34. Esnouf, R.M. J. Mol. Graph. 15, 132–134 (1997).

    Article  CAS  Google Scholar 

  35. Merritt, E.A. & Bacon, D.J. Methods Enzymol. 277, 505–524 (1997).

    Article  CAS  Google Scholar 

  36. Lu, G. J. Appl. Crystallogr. 33, 176–183 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a National Institute of Allergy and Infectious Diseases grant (to J.S.B.).

Author information

Author notes

  1. Farah Javid-Majd

    Present address: Department of Chemistry, Texas A & M University, College Station, Texas, 77842, USA

Authors and Affiliations

  1. Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Matthew W. Vetting, Subray S. Hegde, Farah Javid-Majd, John S. Blanchard & Steven L. Roderick

Authors
  1. Matthew W. Vetting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subray S. Hegde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farah Javid-Majd
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John S. Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven L. Roderick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to John S. Blanchard or Steven L. Roderick.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vetting, M., Hegde, S., Javid-Majd, F. et al. Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates. Nat Struct Mol Biol 9, 653–658 (2002). https://doi.org/10.1038/nsb830

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb830

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing