Skip to main content
SpringerLink
Log in

Superoxide Generation from Nitric Oxide Synthase

Role of cofactors and protein-interaction

  • Chapter
Biomedical EPR, Part A: Free Radicals, Metals, Medicine, and Physiology

Part of the book series: Biological Magnetic Resonance ((BIMR,volume 23))

Abstract

Application of the loop gap resonator technology and improvement in spin trapping methodologies have enormously increased our understanding of the mechanisms of superoxide formation from nitric oxide synthases. In this chapter we discuss the key role of cofactors such as tetrahydrobiopterin and protein-protein interactions in superoxide release from endothelial NOS. The pathophysiological effects of NOS-mediated superoxide generation in cardiovascular system are discussed.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
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.

4. References

  • Abu-Soud, H.M., Ichimori, K., Presta, A. and Stuehr, D.J., 2000, Electron transfer, oxygen binding and nitric oxide feedback inhibition in endothelial nitric oxide synthase. J. Biol. Chem. 275: 17349–17357.

    CAS  PubMed  Google Scholar 

  • Bec, N., Gorren, A.C.F., Voelker, C., Mayer, B. and Lange, R., 1998, Reaction of neuronal nitric-oxide with oxygen at low temperature. Evidence for reductive activation of the oxyferrous complex by tetrahydrobiopterin. J. Biol. Chem. 273: 13502–13508.

    Article  CAS  PubMed  Google Scholar 

  • Bender, A.T., Silverstein, A.M., Demady, D.R., Kanelakis, K.C., Noguchi, S., Pratt, W.B., and Osawa, Y., 1999, Neuronal nitric oxide synthase is regulated by the hsp90-based chaperone system in vivo. J. Biol. Chem. 274: 1472–1478.

    Article  CAS  PubMed  Google Scholar 

  • Boulanger, C.M. and Vanhoutte, P.M., 1997, G-proteins and endothelium-dependent relaxations, J.Vasc. Res. 34: 175–185.

    CAS  PubMed  Google Scholar 

  • Brouet, A., Sonveaux, P., Dessy, C., Moniotte, S., Balligand, J-L., and Feron, O., 2001, HSP90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins. Circ. Res. 89: 866–873.

    CAS  PubMed  Google Scholar 

  • Couture, M., Stuehr, D.J., and Rousseau, D.L., 2000, The ferrous dioxygen complex of the oxygenase domain of neuronal nitric oxide synthase. J. Biol. Chem. 275: 3201–3205.

    Article  CAS  PubMed  Google Scholar 

  • Crane, B.R., Arvai, A.S., Gachhui, R., Wu, C., Ghosh, D.K., Getzoff, E.D., Stuehr, D.J., and Tainer, J.A., 1997, The structure of nitric oxide synthase oxygenase domain and inhibitor complexes. Science 278: 425–431.

    Article  CAS  PubMed  Google Scholar 

  • Dawson, T.M., Bredt, D.S., Fotuhi, M., Hwang, P.M., Snyder, S.H., 1991, Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. USA 88:7797–7801.

    CAS  PubMed  Google Scholar 

  • Fang, M., Jaffrey, S.R., Sawa, A., Ye, K., Luo, X., and Snyder, S.H., 2000, Dexras: A G-protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 28: 183–193.

    Article  CAS  PubMed  Google Scholar 

  • Feldman, P.L., Griffith, O.W., and Stuehr, D.J., 1993, The surprising life of nitric oxide. Chem. & Eng. News (Dec. 20) 26–38.

    Google Scholar 

  • Feron, O., Belhassen, L., Kobzik, L., Smith, T.W., Kelly, R.A. and Michel, T., 1996, Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J. Biol. Chem. 271: 22810–22814.

    CAS  PubMed  Google Scholar 

  • Feron, O., Sladana, F., Michel, J.B., and Michel, T., 1998, The endothelial nitric-oxide synthase-caveolin regulatory cycle. J. Biol. Chem. 273: 3125–3128.

    CAS  PubMed  Google Scholar 

  • Frejaville, C., Karoui, H., Tuccio, B., LeMoigne, F., Culcasi, M., Pietri, S., Lauricella, R. and Tordo, P., 1995, 5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide: a new efficient phosphorylated nitrone for the in vitro and in vivo spin trapping of superoxide. J. Med. Chem. 38: 258–265.

    Article  CAS  PubMed  Google Scholar 

  • Froncisz, W., and Hyde, J.S., 1992, The loop gap resonator: a new microwave lumped circuit ESR sample structure. J. Magn. Res. 47: 515–521.

    Google Scholar 

  • Garcia-Cardeña, G., Martásek, P., Masters, B.S.S., Skidd, P.M., Couet, J, Li, S., Lisanti, M.P., and Sessa, W.C., 1997, Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the NOS caveolin binding domain in vivo. J. Biol. Chem. 272: 25437–25440.

    PubMed  Google Scholar 

  • Garcia-Cardeña, G., Fan, R., Shah, V., Sorrentino, R., Cirino, G., Papapetropoulos, A., and Sessa, W.C., 1998, Dynamic activation of endothelial nitric oxide synthase by HSP90. Nature 392: 821–824.

    PubMed  Google Scholar 

  • Gachhui, R., Presta, A., Bentley, D.F., Abu-Soud, H.M., McArthur, R., Brudvig, G., Ghosh, D.K., and Stuehr, D.J., 1996, Characterization of the reductase domain of rat neuronal nitric oxide synthase generated in the methylotrophic yeast pichia pastoris. Calmodulin response is complete within the reductase domain itself. J. Biol. Chem. 271: 20594–20602.

    CAS  PubMed  Google Scholar 

  • Ghosh, S., Gachhui, R., Crooks, C., Wu, C., Lisanti, M.P., and Stuehr, D.J., 1998, Interaction between caveolin-1 and the reductase domain of endothelial nitric oxide synthase. J. Biol. Chem. 273: 22267–22271.

    CAS  PubMed  Google Scholar 

  • Giovanelli, J., Campos, K.L., and Kaufman, S., 1991, Tetrahydrobiopterin, a cofactor for rat cerebellar nitric oxide synthase, does not function as a reactant in the oxygenation of arginine. Proc. Natl. Acad. Sci. USA 88: 7091–7095.

    CAS  PubMed  Google Scholar 

  • Golser, R., Gorren, A.C.F., Leber, A., Andrew, P., Habish, H-J., Werner, E.R., Schmidt, K., Venema, R.C. and Mayer, B., 2000, Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an autoinhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation. J. Biol. Chem. 275:5291–5296.

    Article  CAS  PubMed  Google Scholar 

  • Gratton, J.P., Fontana, J., O’Connor, D.S., Garcia-Cardena, G., McCabe, T.J., and Sessa, W.C., 2000, Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1. J. Biol. Chem. 275: 22268–22272.

    Article  CAS  PubMed  Google Scholar 

  • Griffith, O.W., and Stuehr, D.J., 1995, Nitric oxide synthases: properties and catalytic mechanism. Ann. Rev. Physiol. 57: 707–736.

    CAS  Google Scholar 

  • Heinzel, B., John, M., Klatt, P., Bohme, E. and Mayer, B., 1992, Ca2+/calmodulin-dependent formation of hydrogen peroxide brain nitric oxide. Biochem. J. 281: 627–630.

    CAS  PubMed  Google Scholar 

  • Jaffrey, S.R., and Snyder, S.H., 1996, PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science 274: 774–777.

    Article  CAS  PubMed  Google Scholar 

  • Jaffrey, S.R., Snowman, A.M., Eliasson, M.J.L., Cohen, N.A., and Snyder, S.H., 1998, CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 20: 115–124.

    Article  CAS  PubMed  Google Scholar 

  • Ju, H, Zou, R., Venema, V.J., and Venema, R.C., 1997, Direct interaction of endothelial nitric oxide synthase and caveolin-1 inhibits synthase activity. J. Biol. Chem. 272: 18522–18525.

    CAS  PubMed  Google Scholar 

  • Kappock, T.J., and Caradonna, J.P., 1996, Pterin-dependent amino acid hydroxylases. Chem. Rev. 96: 2659–2756.

    Article  CAS  PubMed  Google Scholar 

  • Katusic, Z., 2001, Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am. J. Physiol. Heart Circ. Physiol. 281: H981–H986.

    CAS  PubMed  Google Scholar 

  • Kaufman, S., 1995, Tyrosine hydroxylase. In: Advances in Enzymology & Related Areas of Molecular Biology 70: 103–220.

    CAS  Google Scholar 

  • Ledbetter, A.P., McMillan, K., Roman, L.J., Masters, B.S.S., Dawson, J.H., and Sono, M., 1999, Low-temperature stabilization and spectroscopic characterization of the dioxygen complex of the ferrous neuronal nitric oxide synthase oxygenase domain. Biochemistry 38: 8014–8021.

    Article  CAS  PubMed  Google Scholar 

  • Lin, S., Fagan, K.A., Li, K-X., Shaul, P.W., Cooper, D.M.F., and Rodman, D.M., 2000, Sustained endothelial nitric oxide synthase activation requires capacitative Ca2+ entry. J. Biol. Chem. 275: 17979–17985.

    CAS  PubMed  Google Scholar 

  • List, B.M., Klosch, B., Volker, C., Gorren, A.C.F., Sessa, W.C., Werner, E.R., Kukovetz, W.R., Schmidt, K., and Mayer, B., 1997, Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. Biochem J. 323: 159–165.

    CAS  PubMed  Google Scholar 

  • Mansuy, D., and Renaud, J-P., 1995, Heme-thiolate proteins different from cytochromes P450 catalyzing monooxygenations. In: Cytochrome P450: Structure, Mechanism and Biochemistry (Ortiz de Montellano P, Ed.). Pp 537–574. Plenum Press, New York.

    Google Scholar 

  • Martásek, P., Liu, Q., Liu, J., Roman, L.J., Gross, S.S., Sessa, W.C., Masters, B.S., 1996, Characterization of bovine endothelial nitric oxide synthase expressed in E. coli. Biochem. Biophys. Res. Commun. 219:359–365.

    PubMed  Google Scholar 

  • McCabe, T.J., Fulton, D., Roman, L.J., and Sessa, W.C., 2000, Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J. Biol. Chem. 275: 6123–6128.

    Article  CAS  PubMed  Google Scholar 

  • Michel, J.B., Feron, O., Sacks, D. and Michel, T., 1997, Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J. Biol, Chem. 272: 15583–15586.

    CAS  Google Scholar 

  • Miller, T.R., Martásek, P., Omura, T., and Masters, B.S.S., 1999, Rapid kinetic studies of electron transfer in the three isoforms of nitric oxide synthase. Biochem. Biophys. Res. Commun. 265: 184–188.

    Article  CAS  PubMed  Google Scholar 

  • Nathan, C., and Xie, Q-W., 1994, Regulation of biosynthesis of nitric oxide. J. Biol. Chem. 269: 13725–13728.

    CAS  PubMed  Google Scholar 

  • Nishida, C.R., and Ortiz de Montellano, P.R., 1999, Autoinhibition of endothelial nitric-oxide synthase. Identification of an electron transfer control element. J. Biol. Chem. 274: 14692–14698.

    CAS  PubMed  Google Scholar 

  • Olive, G., Mercier, A., LeMoigne, F., Rockenbauer, A., and Tordo, P., 2000, 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide: evaluation of the spin trapping properties. Free Radical Biol. Med. 28: 403–408.

    Article  CAS  Google Scholar 

  • Ortiz de Montellano, P.R., Nishida, C., Rodriguez-Crespo, I., and Gerber, N., 1998, Nitric oxide synthase structure and electron transfer. Drug Metab. Disp. 26: 1185–1189.

    Google Scholar 

  • Pou, S., Pou, W.S., Bredt, D.S., Snyder, S.H., and Rosen, G.M., 1992, Generation of superoxide by purified brain nitric oxide synthase. J. Biol. Chem. 267: 24173–24176.

    CAS  PubMed  Google Scholar 

  • Raman, C.S., Li, H., Martásek, P., Kral, V., Masters, B.S. and Poulos, T.L., 1998, Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell. 95: 939–950.

    Article  CAS  PubMed  Google Scholar 

  • Raman, C.S., Martásek, P., and Masters, B.S.S., 2000, Structural themes determining function in nitric oxide synthases. In: The porphyrin handbook. (Kadish KM, Smith KM, Guilard R, Eds) Vol. 4/Biochemistry and binding: activation of small molecules, Pp. 293–339, Academic Press, London.

    Google Scholar 

  • Roman, L.J., Sheta, E.A., Martasek, P., Gross, S.S., Liu, Q., Masters, B.S., 1995, High-level expression of functional rat neuronal nitric oxide synthase in Escherichia coli. Proc. Natl. Acad. Sci. USA 92:8428–8432.

    CAS  PubMed  Google Scholar 

  • Roman, L.J., Martásek, P., Miller, R.T., Harris, D.E., de la Garza, M.A., Shea, T.M., Kim, JJP, and Masters, B.S.S., 2000, The C termini of constitutive nitric oxide synthase control electron flow through the flavin and heme domains and affect modulation by calmodulin. J. Biol. Chem. 275: 29255–29232.

    Google Scholar 

  • Roubaud, V., Sankarapandi, S., Kuppusamy, P., Tordo, P., and Zweier, J.L., 1997, Quantitative measurement of superoxide generation using spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide. Anal. Biochem. 247: 404–411.

    Article  CAS  PubMed  Google Scholar 

  • Russell, K.S., Haynes, M.P., Caulin-Glaser, T., Rosneck, J., Sessa, W.C., and Bender, J.R., 2000, Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. Effects on calcium and NO release. J. Biol. Chem. 275, 5026–5030.

    Article  CAS  PubMed  Google Scholar 

  • Salerno, J.C., Martásek, P., Roman, L.J., and Masters, B.S.S., 1996, Electron paramagnetic resonance spectroscopy of the heme domain of inducible nitric oxide synthase: binding of ligands at the arginine site induces changes in the heme ligand geometry. Biochemistry 35: 7616–7630.

    Google Scholar 

  • Salerno, J.C., Harris, D.E., Irizarry, K., Patel, B., Morales, A.J., Smith, S.M., Martásek, P., Roman, L.J., Masters, B.S.S., Jones, C.L., Weissman, B.A., Liu, Q. and Gross, S.S., 1997, An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase. J. Biol. Chem. 272: 29769–29777.

    Article  CAS  PubMed  Google Scholar 

  • Santolini, J., Adak, S., Curran, C.M.L., and Stuehr, D.J., 2001, A kinetic stimulation model that describes catalysis and regulation in nitric oxide synthase. J. Biol. Chem. 276: 1233–1243.

    CAS  PubMed  Google Scholar 

  • Sattler, R., Xiong, Z., Lu, W-Y., Hafner, M., McDonald, J.F., and Tymianski, M., 1999, Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284: 1845–1848.

    Article  CAS  PubMed  Google Scholar 

  • Schmidt, H.H.H.W., Smith, R.M., Nakane, M., and Murad, F., 1992, Ca2+/calmodulin-dependent NO synthase Type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities. Biochemistry 31: 3243–3249.

    CAS  PubMed  Google Scholar 

  • Song, Y., Zweier, J.L., and Xia, Y., 2001, Heat-shock protein 90 augments neuronal nitric oxide synthase activity by enhancing Ca2+/calrnodulin binding Biochem J. 355: 357–360.

    Article  CAS  PubMed  Google Scholar 

  • Sowa, G., Pypaert, M. and Sessa, W.C., 2001, Distinction between signaling mechanism in lipid rafts vs. caveolae. Proc. Natl. Acad. Sci. USA 98: 14072–14077.

    Article  CAS  PubMed  Google Scholar 

  • Vásquez-Vivar, J., Hogg, N., Pritchard, K.A. Jr., Martásek, P., and Kalyanaraman, B., 1997a, Superoxide anion formation from lucigenin: an electron paramagnetic resonance spin trapping study. FEBS Lett.. 403: 127–130.

    PubMed  Google Scholar 

  • Vásquez-Vivar, J., Martásek, P., Hogg, N., Masters, B.S.S., Pritchard, K.A. Jr, and Kalyanaraman, B., 1997b, Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 36: 11293–11297.

    PubMed  Google Scholar 

  • Vásquez-Vivar, J., Kalyanarman, B., Mártasek, P., Hogg, N., Masters, B.S.S., Karoui, H., Pritchard, K.A. Jr., 1998, Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc. Natl. Acad. Sci USA 95: 9220–9225.

    PubMed  Google Scholar 

  • Vásquez-Vivar, J., Martásek, P., Hogg, N., Karoui, H., Masters, B.S.S., Pritchard, K.A. Jr and Kalyanaraman, B., 1999a, Electron spin resonance spin-trapping detection of superoxide generated by neuronal nitric oxide synthase. Methods Enzymol. 301: 169–177.

    PubMed  Google Scholar 

  • Vásquez-Vivar, J., Hogg, N., Martásek, P., Karoui, H., Pritchard, K.A. Jr., and Kalyanaraman, B., 1999b, Tetrahydrobiopterin-dependent inhibition of superoxide generation from neuronal nitric oxide synthase. J. Biol. Chem. 274: 26736–26742.

    PubMed  Google Scholar 

  • Vásquez-Vivar, J., Whitsett, J., Martásek, P., Hogg, N., and Kalyanaraman, B., 2001, Reaction of tetrahydrobiopterin with superoxide: EPR kinetic analysis and characterization of the pteridine radical. Free Radical Biol. Med. 31: 975–985.

    Google Scholar 

  • Vásquez-Vivar, J., Martásek, P., Whitsett, J., Joseph, J., and Kalyanaraman, B., 2002a, The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem J. 362:723–739.

    Google Scholar 

  • Vásquez-Vivar, J., Duquaine, D., Whitsett, J., Kalyanaraman, B., and Rajagopalan S., 2002b, Altered tetrahydrobiopterin metabolism in Atherosclerosis. Implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants. Arterioscler. Thromb. Vasc. Biol. 22: (in press).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226

    Jeannette Vásquez-Vivar & B. Kalyanaraman

  2. Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226

    Jeannette Vásquez-Vivar & B. Kalyanaraman

  3. Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, 78284, USA

    Pavel Martásek

Authors
  1. Jeannette Vásquez-Vivar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pavel Martásek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Kalyanaraman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Denver, Denver, Colorado

    Sandra R. Eaton , Gareth R. Eaton  & Lawrence J. Berliner ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science + Business Media, Inc.

About this chapter

Cite this chapter

Vásquez-Vivar, J., Martásek, P., Kalyanaraman, B. (2005). Superoxide Generation from Nitric Oxide Synthase. In: Eaton, S.R., Eaton, G.R., Berliner, L.J. (eds) Biomedical EPR, Part A: Free Radicals, Metals, Medicine, and Physiology. Biological Magnetic Resonance, vol 23. Springer, Boston, MA. https://doi.org/10.1007/0-387-26741-7_4

Download citation

  • DOI: https://doi.org/10.1007/0-387-26741-7_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-48506-0

  • Online ISBN: 978-0-387-26741-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation