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:

Arginase–boronic acid complex highlights a physiological role in erectile function

Nature Structural Biology volume 6, pages 1043–1047 (1999)Cite this article

Abstract

The crystal structure of the complex between the binuclear manganese metalloenzyme arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-boronohexanoic acid (ABH), has been determined at 1.7 Å resolution from a crystal perfectly twinned by hemihedry. ABH binds as the tetrahedral boronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear manganese cluster and a second hydroxyl oxygen coordinating to Mn2+A. This binding mode mimics the transition state of a metal-activated hydroxide mechanism. This transition state structure differs from that occurring in NO biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also show that arginase activity is present in the penis. Accordingly, the tight binding and specificity of ABH allows us to probe the physiological role of arginase in modulating the NO-dependent smooth muscle relaxation required for erection. Strikingly, ABH causes significant enhancement of nonadrenergic, noncholinergic nerve-mediated relaxation of penile corpus cavernosum smooth muscle, suggesting that arginase inhibition sustains L-arginine concentrations for NO synthase activity. Therefore, human penile arginase is a potential target for therapeutic intervention in the treatment of erectile dysfunction.

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: L-Arginine catabolism.
Figure 2: Arginase–ABH complex.
Figure 3: Enzymology of NO synthase and arginase.
Figure 4: Effect of ABH on NANC nerve-mediated relaxation in penile corpus cavernosum smooth muscle.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Feldman, H. A., Goldstein, I., Hatzichristou, D. G., Krane, R. J & McKinlay, J. B. J. Urol. 151, 54–61 (1994).

    Article  CAS  Google Scholar 

  2. Ignarro, L. J. et al. Biochem. Biophys. Res. Commun. 170, 843–850 (1990).

    Article  CAS  Google Scholar 

  3. Kim, N., Azadzoi, K. M., Goldstein, I. & Saenz de Tejada, I. J. Clin. Invest. 88, 112–118 (1991).

    Article  CAS  Google Scholar 

  4. Burnett, A. L., Chang, T. S. K., Lowenstein, C. J., Bredt, D. S. & Snyder, S. H. Science 257, 401–403 (1992).

    Article  CAS  Google Scholar 

  5. Rajfer, J., Aronson, W. J., Bush, P. A., Dorey, F. J. & Ignarro, L. J. New Engl. J. Med. 238, 90–94 (1992).

    Article  Google Scholar 

  6. Burnett, A. L. J. Urol. 157, 320–324 ( 1997).

    Article  CAS  Google Scholar 

  7. Reczkowski, R. S. & Ash, D. E. J. Am. Chem. Soc. 114, 10992–10994 ( 1992).

    Article  CAS  Google Scholar 

  8. Cavalli, R. C., Burke, C. J., Kawamoto, S., Soprano, D. R. & Ash, D. E. Biochemistry 33, 10652–10657 (1994).

    Article  CAS  Google Scholar 

  9. Ash, D. E., Cox, J. D. & Christianson, D. W. In Manganese and its role in biological processes, Vol. 37 of Metal ions in biological systems, Sigel A. & Sigel H., Eds.; New York: M. Dekker, 408–428.

  10. Albina, J. E., Mills, C. D., Henry, W. L. & Caldwell, M. D. J. Immunol. 144, 3877–3880 (1990).

    CAS  Google Scholar 

  11. Wang, W. W. et al. Biochem. Biophys. Res. Commun. 210, 1009–1016 (1995).

    Article  CAS  Google Scholar 

  12. Chakder, S. & Rattan, S. Am. J. Physiol. 264, G7–G12 (1993).

    CAS  PubMed  Google Scholar 

  13. Chakder, S. & Rattan, S. J. Pharmacol. Exp. Ther. 282, 378–384 (1997).

    CAS  PubMed  Google Scholar 

  14. Baggio, R. et al. J. Pharmacol. Exp. Ther. 290, 1409– 1416 (1999).

    CAS  PubMed  Google Scholar 

  15. Baggio, R. et al. J. Am. Chem. Soc. 119, 8107– 8108 (1997).

    Article  CAS  Google Scholar 

  16. Kanyo, Z. F., Scolnick, L. R., Ash, D. E. & Christianson, D. W. Nature 383, 554–557 ( 1996).

    Article  CAS  Google Scholar 

  17. Kettner, C. A. & Shenvi, A. B. J. Biol. Chem. 259, 15106–15114 ( 1984).

    CAS  PubMed  Google Scholar 

  18. Shenvi, A. B. Biochemistry 25, 1286–1291 (1986).

    Article  CAS  Google Scholar 

  19. Yeates, T. O. Methods Enzymol. 276, 344–358 (1997).

    Article  CAS  Google Scholar 

  20. Redinbo, M. R. & Yeates, T. O. Acta Crystallogr. D49, 375–380 ( 1993).

    CAS  Google Scholar 

  21. Brünger, A. T. et al. Acta Crystallogr. D54, 905– 921 (1998).

    Google Scholar 

  22. Bewley, M. C., Jeffrey, P. D., Patchett, M. L., Kanyo, Z. F. & Baker, E. N. Structure 7, 435–448 (1999).

    Article  CAS  Google Scholar 

  23. Reczkowski, R. S. & Ash, D. E. Arch. Biochem. Biophys. 312, 31–37 ( 1994).

    Article  CAS  Google Scholar 

  24. Stuehr, D. J. & Griffith, O. W. Adv. Enzymol. 65, 287–346 (1992).

    CAS  PubMed  Google Scholar 

  25. Saenz de Tejada, I. et al. Am. J. Physiol. 254, H459– H467 (1988).

    Article  CAS  Google Scholar 

  26. Moody, J. A., Vernet, D., Laidlaw, S., Rajfer, J. & Gonzalez-Cadavid, N. F. J. Urol. 158, 942– 947 (1997).

    Article  CAS  Google Scholar 

  27. Wheeler, M. A., Smith, S. D., Saito, N., Foster, H. E. Jr. & Weiss, R. M. J. Urol. 158, 2045–2050 (1997).

    Article  CAS  Google Scholar 

  28. Zorgniotti, A. W. & Lizza, E. F. Int. J. Impotence Res. 6, 33–35 ( 1994).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Navaza, J. Acta Crystallogr. A50, 157–163 (1994).

    Article  CAS  Google Scholar 

  31. Jones, T. A., Zou, J.-Y., Cowan, S. W. & Kjeldgaard, M. Acta. Crystallogr. A47, 110–119 ( 1991).i.

    Article  CAS  Google Scholar 

  32. Verdon, C. P., Burton, B. A. & Prior, R. L. Anal. Biochem. 224, 502– 508 (1995).

    Article  CAS  Google Scholar 

  33. Rüegg, U. T. & Russell, A. S. Anal. Biochem. 102, 206–212 ( 1980).

    Article  Google Scholar 

  34. Esnouf, R. M. J. Mol. Graphics 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 

Download references

Acknowledgements

We thank D. E. Ash, R. Baggio, K. Gauvreau, C. A. Lesburg, R. Marmorstein, M. Redinbo, T. Stams, R. Trievel, and T. Yeates for helpful discussions during the course of this investigation, and we thank P. Adams and A. Brünger for modifications to the refinement program CNS. This work is supported by grants to A.M.T. and D.W.C. from the National Institutes of Health and is based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS) with the use of the Macromolecular Diffraction at CHESS (MacCHESS) facility.

Author information

Authors and Affiliations

  1. Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, 19104-6323, Pennsylvania, USA

    J. David Cox & David W. Christianson

  2. Departments of Urology and Biochemistry, Boston University School of Medicine, 700 Albany Street, Boston, 02118, Massachusetts, USA

    Noel N. Kim & Abdulmaged M. Traish

Authors
  1. J. David Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noel N. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdulmaged M. Traish
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David W. Christianson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Christianson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cox, J., Kim, N., Traish, A. et al. Arginase–boronic acid complex highlights a physiological role in erectile function. Nat Struct Mol Biol 6, 1043–1047 (1999). https://doi.org/10.1038/14929

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/14929

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