Skip to main content

Reactive Nitrogen Species and Proteins: Biological Significance and Clinical Relevance

  • Chapter
Biological Reactive Intermediates VI

Abstract

Nitric oxide and reactive nitrogen species such as nitrogen dioxide, dinitrogen trioxide and peroxynitrite react selectively with different proteins causing covalent structural modifications that alter protein function (1–3). The predominant post-translational modification mediated by nitric oxide is the S-nitrosylation of cysteine residues whereas reactive nitrogen intermediates primarily oxidize cysteine and nitrate tyrosine residues. Glyceraldehyde-3-phosphate dehydrogenase, ryanodine receptor, p21ras, hemoglobin and caspase 3 are modified by Snitrosylation of cysteine residues in vivo (4–10). The S-nitrosylation of the cysteine residues provides a selective and reversible covalent modification that regulates protein function and explains the ability of nitric oxide to regulate simultaneously different cellular pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Stamler, J.S., Toone, E.J., Lip[ton, S.A. and Sucher, N.J. (1997)(S)NO signals: Translocation, regualtion and a consensus motif.Neuron 18,691–696

    Article  PubMed  CAS  Google Scholar 

  2. Simon, D.I., Mullins, M.E., Jia, L., Gaston, B., Singel, D.J., and Stamler, J.S. (1996) Polynitrosylated proteins: Characterization, bioactivity, and functional consequences. Proc. Natl. Acad. Sci. USA 93, 4736–4741

    Article  PubMed  CAS  Google Scholar 

  3. Ischiropoulos, H. (1998). Biological Tyrosine Nitration-A pathophysiological function of nitric oxide and reactive oxygen species. Arch. Biochem. Biophys. 356, 1–11.

    Article  PubMed  CAS  Google Scholar 

  4. Molina y Vedia, L., McDonald, B., Reep, B., Brune, B., Di Silvio, M., Billiar, T.R. and Lapetina, E.G. (1992) Nitric Oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation. J Biol. Chem. 267:24929–24932.

    PubMed  CAS  Google Scholar 

  5. Lander, H.M., Milbank, A.J., Tauras, J.M., Hajjar, D.P., Hempstead, B.L., Schwartz, G.D., Kraemer, R.T., Mirza, U.A., Chalt, B.T., Burk, S.C., and Quilliam, L.A. (1996) Redox regulation of cell signalling. Nature 381, 380–381.

    Article  PubMed  CAS  Google Scholar 

  6. Xu, L., Eu, J.P., Msissner, G., and Stamler, J.S. (1998) Activation of the cardiac calcium Release Channel (Ryanodine Receptor) by Poly-S-Nitrosylation. Science 279, 234–237.

    Article  PubMed  CAS  Google Scholar 

  7. Lipton, S.A., Choi, Y.-B., Pan, Z.-H., Lei, S.Z., Chen, H-S.V., Sucher, N.J., Loscalzo, J., Singel, D.J. and Stamler, J.S. (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632.

    Article  PubMed  CAS  Google Scholar 

  8. Gow, A. and Stamler, J. (1998) Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 391, 169–173.

    Article  PubMed  CAS  Google Scholar 

  9. Kim YM, Talanian RV, and Billiar TR (1997) Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J. Biol. Chem. 272, 31138–31148.

    Article  PubMed  CAS  Google Scholar 

  10. Mannick, J.B., Hausladen, A., Liu, L., Hess, D.T., Zeng, M., Miao, Q.X., Kane, L.S., Gow, A.J. and Stamler, J.S. (1999) Fas-induced caspase denitrosylation. Science 284, 651–654.

    Article  PubMed  CAS  Google Scholar 

  11. MacMillan-Crow, L.A., Crow, J.P., Kerby, J.D., Beckman, J.S. and Thompson, J.A. (1996) Nitration and inactivation of Mn superoxide dismutase in chronic rejection of human renal allografts. Proc. Natl. Acad. Sci. USA. 93, 11853–11858.

    Article  PubMed  CAS  Google Scholar 

  12. Zhou, M-H, Klein, T., Pasquet, J-P. and Ullrich, V. (1998) Interleukin-1β decreases prostacyclin synthase activity in rat mesanglial cells via endogenous peroxynitrite formation. Biochem. J. 336, 507–512.

    Google Scholar 

  13. Viner R1, Ferrington DA, Huhmer AFR, Bigelow DJ, and Schoneich C (1996) Accumulation of nitrotyrosine on the SERCA2a isoform of SR Ca-ATPase of rat skeletal muscle during aging: a peroxynitrite-mediated process? FEBS Lett. 379, 286–290.

    Article  PubMed  CAS  Google Scholar 

  14. Klebl, B.M., Ayoub, A.T. and Pette, D. (1998) Protein oxidation, tyrosine nitration, and inactivation of sarcoplasmic reticulum Ca2+-ATPase in low-frequency stimulated rabbit muscle. FEBS Lett. 422, 381–384.

    Article  PubMed  CAS  Google Scholar 

  15. Ara, J., Przedborski, S., Naini, A.B., Jackson-Lewis, V., Trifiletti, R.R., Horwitz, J. and Ischiropoulos, H. (1998) Inactivation of tyrosine hydroxylase following exposure to peroxynitrite and MPTP. Proc. Natl. Acad. Sci. USA. 95, 7659–7663.

    Article  PubMed  CAS  Google Scholar 

  16. Boota A, Zar H, Kim Y-M, Johnson B, Pitt B, Davies P (1996) IL-1P. stimulates superoxide and delayed peroxynitrite production by pulmonary vascular smooth muscle cells. Am. J. Physiol. 271, L932–L938.

    PubMed  CAS  Google Scholar 

  17. Gole, M.D., Souza, J.M., Choi, I., Malcolm, S., Hertkom, C., Foust III, R.F., Finkel, B. Lanken, P.F. and Ischiropoulos, H. (2000) Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome. Am. J. Physiol., 278, L961–967.

    Google Scholar 

  18. Souza, J.M., Giasson, B.I., Chen, Q. Lee, V.M-Y. and Ischiropoulos, H. (2000) Dityrosine Cross-linking Promotes Formation of Stable a-synuclein Polymers: Implication of Nitrative and Oxidative Stress in the Pathogenesis of Neurodegenerative Synucleinopathies. J. Biol. Chem. 275, 18344–18349, 2000.

    Article  PubMed  CAS  Google Scholar 

  19. Furchgott. R.F. (1996) The discovery of EDRF and its importance in the identification of nitric oxide. JAMA 276, 1186–1188.

    CAS  Google Scholar 

  20. Moore, E.G. and Gibson, Q.H. (1976) Cooperativity in the dissociation of nitric oxide from hemoglobin. J Biol. Chem. 251, 2788–2794.

    PubMed  CAS  Google Scholar 

  21. Craven, P.A. and DeRubertis, F.R. (1978) Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemeproteins. J Biol. Chem. 253, 8433–8443.

    PubMed  CAS  Google Scholar 

  22. Lancaster Jr., J.R., Langrehr, J.M., Bergonia, H.A., Murase, N., Simmons, R.L., and Hoffman, R.A. (1992) EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft. J. Biol. Chem. 267, 10994–10998.

    PubMed  CAS  Google Scholar 

  23. Ribeiro, J.M.C., Hazzard, J.M.H., Nussenzveig, R.H., Champagne, D.E., and Walker, F.A. (1993) Reversible binding of nitric oxide by a salivary heme protein from a bloodsucking insect. Science 260, 539–541.

    Article  PubMed  CAS  Google Scholar 

  24. Gardner, P.R., Gardner, A.M., Martin, L.A., and Salzman, A.L. (1998) Nitric oxide dioxygenase: An enzymic function for flavohemoglobin. Proc. Natl. Acad. Sci. USA 95, 10378–10383.

    Article  PubMed  CAS  Google Scholar 

  25. Hausladen, A., Gow, A.J., and Stamler, J.S. (1998) Nitrosative stress: Metabolic pathway involving the flavohemoglobin. Proc. Natl. Acad. Sci. USA 95, 14100–14105.

    Article  PubMed  CAS  Google Scholar 

  26. Tsubaki, M., Hiwatashi, A., Ichikawa, Y. and Hori, H. (1987) EPR study of ferrous cytocrome P450scc-nitric oxide complexes: effects of cholesterol and its analogues. Biochemistry 26, 4527–4534.

    Article  PubMed  CAS  Google Scholar 

  27. Kennedy, M.C., Antholine, W.E., and Beinert, H. (1997) An EPR investigation of the products of the reaction of cytosolic and mitochondrial aconitase with nitric oxide. J. Biol. Chem. 272, 20340–20347.

    Article  PubMed  CAS  Google Scholar 

  28. Pearce, L.L., Gandley, R.E., Han, W., Wasserloos, K., Stitt, M., Kanai, A.J., McLaughlin, M.K., Pitt, B.R., and Levitan, E.S. (2000) Role of metallothionein in nitric oxide signaling as revealed by a green fluorescent fusion protein. Proc. Natl. Acad. Sci. 97, 477–482.

    Article  PubMed  CAS  Google Scholar 

  29. Cassina, A and Radi, R. (1996) Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem. Biophys. 328, 309–316.

    CAS  Google Scholar 

  30. Bouton, C., Raveau, M., and Drapier, J.C. (1996) Modulation of iron regulatory protein functions. J. Biol. Chem. 271, 2300–2306.

    Article  PubMed  CAS  Google Scholar 

  31. Gunthers, M.R., Hsi, L.C., Curtis, J.F., Giorse, J.K., Marnett. L.J., Eling, T.E., and Mason, R.P. (1997) Nitric oxide trapping of the tyrosyl radical of Prostaglandin H Synthase-2 leads to tyrosine iminoxyl radical and nitrotyrosine formation. J. Biol. Chem. 272, 17086–17090.

    Article  Google Scholar 

  32. Goodwin, D.C., Gunthers, M.R., Hsi, L.C., Crews, B.C., Eling, T.E., Mason, R.P., and Marnett, L.J. (1998) Nitric oxide trapping of tyrosyl radicals generated during prostaglandin endoperoxide synthase turnover. J. Biol. Chem. 273, 8903–8909.

    Article  PubMed  CAS  Google Scholar 

  33. Guittet, O., Ducastel, B., Salem, J.S., Henry, Y., Rubin, H., Lemaire, G., and Lepoivre, M. (1998) Differential sensitivity of the tyrosyl radical of mouse ribonucleotide reductase to nitric oxide and peroxynitrite. J. Biol. Chem. 273, 22136–22144.

    Article  PubMed  CAS  Google Scholar 

  34. Gow, A., Buerk, D.G., and Ischiropoulos, H. (1997) A novel reaction mechanism for the formation of S-nitrosothiols in vivo. J. Biol. Chem. 272, 2841–2845.

    Article  PubMed  CAS  Google Scholar 

  35. Koppenol, W.H. (1998) The basic chemistry of nitrogen monoxide and peroxynitrite. Free Rad. Bio. Med. 25, 385–391.

    Article  CAS  Google Scholar 

  36. Boese M, Mordvintcev PI, Vanin AF, Busse R, Mulsch (1995) S-Nitrosation of serum albumin by dinitrosyl-iron complex. J. Biol. Chem. 270, 29244–29249.

    Article  PubMed  CAS  Google Scholar 

  37. Inoue, K., Akaike, T., Miyamoto, Y., Okamoto, T., Sawa, T., Otagiri, M., Suzuki, S., Yoshimura, T., and Maeda, H. (1999) Nitrosothiol formation catalyzed by ceruloplasmin. J. Biol. Chem. 274, 27069–27075.

    Article  PubMed  CAS  Google Scholar 

  38. Liu, X., Miller, M.J., Johshi, M.S., Thomas, D.D. and Lancaster, Jr. J.R. (1998) Accelerated reaction of nitric oxide with oxygen within the hydrophobic interior of biological membranes. Proc. Natl. Acad. Sci. USA 95, 2175–2179.

    Article  PubMed  CAS  Google Scholar 

  39. O’Donnell VB, Eiserich, JP, Chumley, PH, Jablonsky, MJ, Krishna, NR, Kirk, M, Barnes, S, Darley-Usmar, VM, Freeman, BA (1998) Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitric acid, nitrogen dioxide, and nitroniumion. Chem. Res. Toxicol. 12, 83–92

    Article  Google Scholar 

  40. Wink, D.A., Cook, J.A., Kim, S.Y., Vodovotz, Y., Pacelli, R., Krishna, M.C., Russo, A., Mitchell, J.B., Jourd’heuil, D., Miles, A.M. and Grisham, M.B. (1997) Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide-derived reactive intermediates. J. Biol. Chem. 272, 11147–11151.

    Article  PubMed  CAS  Google Scholar 

  41. Van der Vliet, A., Eiserich, J.P., Halliwell, B., and Cross, C.E. Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. J. Biol. Chem. 272:7617–7625, 1997.

    Article  PubMed  Google Scholar 

  42. Wu, W., Chen, Y. and Hazen, S.L. Eosinophil peroxidase nitrates protein tyrosyl residues. J. Biol. Chem. 274:25933–25944, 1999.

    Article  PubMed  CAS  Google Scholar 

  43. Van Dalen, C.J., Winterbourn, C.C., Senthilmohan, R. and Kettle, A.J. (2000) Nitrite as a substrate and inhibitor of myeloperoxidase. J. Biol. Chem. 275, 11638–11644.

    Article  PubMed  Google Scholar 

  44. Ischiropoulos, H., D. Duran, J. Nelson, A.B. Al-Mehdi. (1996) Reactions of nitric oxide and peroxynitrite with organic molecules and ferrihorseradish peroxidase: interference with the determination of hydrogen peroxide. Free Rad. Biol. Med. 20, 373–381.

    Article  PubMed  CAS  Google Scholar 

  45. Sampson, J.B., Ye, Y., Rosen, H. and Beckman, J.S. Myeloperoxidase and horseradish peroxidase catalyze tyrosine nitration in proteins from nitrite and hydrogen peroxide. Arch. Biochem. Biophys. 356, 207–213, 1998.

    Article  PubMed  CAS  Google Scholar 

  46. Schopfer F, Riobo N, Carreras MC, Alvarez B, Radi R, Boveris A, Cadenas E, Poderoso JJ. (2000) Oxidation of ubiquinol by peroxynitrite: implications for protection of mitochondria against nitrosative damage.Biochem J. 349, 35–42.

    Article  PubMed  CAS  Google Scholar 

  47. Souza, J.M., Daikhin, E., Yudkoff, M., Raman’ C.S. and Ischiropoulos, H. Factors determining the selectivity of protein tyrosine nitration. Arch. Biochem. Biophys. 371, 169–178, 1999.

    Article  PubMed  CAS  Google Scholar 

  48. Alvarez, B., Ferrer-Sueta, G., Freeman, B.A., and Radi, R. (1998) Kinetics of peroxynitrite reaction with amino acids and human serum albumin. J. Biol. Chem. 274, 842–848.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Souza, J.M. et al. (2001). Reactive Nitrogen Species and Proteins: Biological Significance and Clinical Relevance. In: Dansette, P.M., et al. Biological Reactive Intermediates VI. Advances in Experimental Medicine and Biology, vol 500. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0667-6_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0667-6_22

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5185-6

  • Online ISBN: 978-1-4615-0667-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics