Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors

Vásquez-Vivar, Jeannette; Kalyanaraman, B.; Martásek, Pavel; Hogg, Neil; Masters, Bettie Sue Siler; Karoui, Hakim; Tordo, Paul; Pritchard, Kirkwood A.

doi:10.1073/pnas.95.16.9220

Cited by 1,484Nitric Oxide and Endothelin EffectsMetal-Catalyzed Oxygenation MechanismsRedox biology and oxidative stress

Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors

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Vásquez-Vivar, Jeannette, Kalyanaraman, B., Martásek, Pavel, Hogg, Neil, Masters, Bettie Sue Siler, Karoui, Hakim, Tordo, Paul, Pritchard, Kirkwood A.·1998·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.95.16.9220PMC PMC21319

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Abstract

The mechanism of superoxide generation by endothelial nitric oxide synthase (eNOS) was investigated by the electron spin resonance spin-trapping technique using 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide. In the absence of calcium/calmodulin, eNOS produces low amounts of superoxide. Upon activating eNOS electron transfer reactions by calcium/calmodulin binding, superoxide formation is increased. Heme-iron ligands, cyanide, imidazole, and the phenyl(diazene)-derived radical inhibit superoxide generation. No inhibition is observed after addition of l -arginine, N G -hydroxy- l -arginine, l -thiocitrulline, and l - N G -monomethyl arginine to activated eNOS. These results demonstrate that superoxide is generated from the oxygenase domain by dissociation of the ferrous–dioxygen complex and that occupation of the l -arginine binding site does not inhibit this process. However, the concomitant addition of l -arginine and tetrahydrobiopterin (BH 4 ) abolishes superoxide generation by eNOS. Under these conditions, l -citrulline production is close to maximal. Our data indicate that BH 4 fully couples l -arginine oxidation to NADPH consumption and prevents dissociation of the ferrous–dioxygen complex. Under these conditions, eNOS does not generate superoxide. The presence of flavins, at concentrations commonly employed in NOS assay systems, enhances superoxide generation from the reductase domain. Our data indicate that modulation of BH 4 concentration may regulate the ratio of superoxide to nitric oxide generated by eNOS.

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In anoxic conditions, eNOS catalyzes nitrite reduction to NO.
“Indeed, in anoxic conditions, eNOS has been shown to catalyze nitrite reduction to NO (970).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [970]

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Authors: Vásquez-Vivar, J., Kalyanaraman, B., Martásek, P., Hogg, N., Masters, B. S. S., Karoui, H., Tordo, P., & Pritchard, K. A.
Affiliations: Cardiovascular Research Center, Department of Pathology, and Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226; Biochemistry Department, University of Texas Health Science Center, San Antonio, TX 78284-7760; and Laboratoire Structure et Réactivité des Espèces Paramagnetiques, Centre National de la Recherche Scientifique Unité de Recherche Associée 1412, Université de Provence, 13397 Marseilles Cedex 20, France
Centre National de la Recherche Scientifique (FR)
ORCID: Kalyanaraman, B.
Hogg, Neil
Karoui, Hakim
Tordo, Paul
Pritchard, Kirkwood A.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1998-08-04
Volume: 95
Issue: 16
Pages: 9220-9225
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.95.16.9220
PMC: PMC21319
OpenAlex: W2026425756
Cited by: 1,484
References: 48
Citations by year: 2026: 11 · 2025: 15 · 2024: 17 · 2023: 25 · 2022: 29 · 2021: 11 · 2020: 23 · 2019: 31 · 2018: 45 · 2017: 43 · 2016: 49 · 2015: 41 · 2014: 77 · 2013: 73 · 2012: 79
FWCI: 28.82
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Welch Foundation (AQ-1192)
American Heart Association
National Institutes of Health (5r29hl045058-03, 5r01gm027665-24, RR 01008, GM55792)
National Heart, Lung, and Blood Institute (HL45058)
National Institute of General Medical Sciences (R29GM055792, R01GM052419, GM 27665, R01GM055792)
National Center for Research Resources (P41RR001008, RR 01008)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: endothelial nitric oxide synthase, superoxide production, tetrahydrobiopterin, L-arginine, oxygenase domain, reductase domain, flavin, citrulline, NADPH consumption, cofactors
MeSH terms: Animals, Arginine, Biopterins, Calcium, Calmodulin, Cattle, Electron Spin Resonance Spectroscopy, NADP, Spin Labels, Superoxides, Nitric Oxide Synthase, NADPH Oxidases, Nitric Oxide Synthase Type III

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Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors

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