Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain

Xia, Yong; Roman, Linda J.; Masters, Bettie Sue S.; Zweier, Jay L.

doi:10.1074/jbc.273.35.22635

Cited by 388Nitric Oxide and Endothelin EffectsMetal-Catalyzed Oxygenation MechanismsHemoglobin structure and function

Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain

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Xia, Yong, Roman, Linda J., Masters, Bettie Sue S., Zweier, Jay L.·1998·Journal of Biological Chemistry

DOI 10.1074/jbc.273.35.22635

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Abstract

In the absence of L-arginine, the heme center of the oxygenase domain of neuronal nitric-oxide synthase reduces molecular oxygen to superoxide (O-2). Our recent work has provided evidence that inducible NOS (iNOS) may also catalyze O-2 formation in macrophages. However, there has been a lack of direct evidence of superoxide generation from the purified iNOS, and it was previously hypothesized that significant O-2 production does not occur. Moreover, the mechanism and enzyme site responsible for O-2 generation is unknown. To determine whether iNOS produces O-2 and to identify the mechanism of this process, we performed electron paramagnetic resonance measurements on purified iNOS using the spin trap 5,5-dimethyl-1-pyrroline N-oxide. In the presence of NADPH, prominent O-2 adduct signals were detected from iNOS. These signals were totally abolished by superoxide dismutase but not affected by catalase. High concentrations of L-arginine decreased this O-2 formation, whereas its enantiomer D-arginine did not. Pre-incubation of iNOS with the flavoprotein inhibitor diphenyleneiodonium totally blocked these O-2 signals. Conversely, pretreatment of the enzyme with the heme blocker cyanide had no effect on O-2 generation. Furthermore, strong O-2 generation was directly detected from the isolated iNOS reductase domain. Together, these data demonstrate that iNOS does generate O-2, and this mainly occurs at the flavin-binding sites of the reductase domain.

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The involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes.
“It seems that the involvement of l-arginine in different metabolic pathways makes the use of l-arginine levels as a biomarker a poor indicator of outcomes (668, 857, 1029).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1029]
l-citrulline has been used to increase l-arginine levels.
“For example, l-citrulline has also been used to increase l-arginine levels (842, 1029).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1029]

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The Characteristics and Regulatory Mechanisms of Superoxide Generation from eNOS Reductase Domain
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Authors: Xia, Y., Roman, L. J., Masters, B. S. S., & Zweier, J. L.
Affiliations: Johns Hopkins University (US)
The University of Texas at San Antonio Health Science Center (US)
Corresponding author: Zweier, Jay L.
ORCID: Xia, Yong
Zweier, Jay L.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1998-08
Volume: 273
Issue: 35
Pages: 22635-22639
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.273.35.22635
OpenAlex: W2064619021
Cited by: 388
References: 29
Citations by year: 2026: 1 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 6 · 2014: 12 · 2013: 18 · 2012: 14
FWCI: 10.43
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8109 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: Welch Foundation (AQ-1192)
American Heart Association
National Institutes of Health (HL38324)
National Heart, Lung, and Blood Institute (HL-38324, HL52315, P50HL052315)
National Institute of General Medical Sciences (R01GM052419, GM-52419)
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 › Cell Biology › Hemoglobin structure and function
Keywords: inducible nitric oxide synthase, superoxide production, oxygenase domain, reductase domain, flavin binding site, L-arginine, diphenyleneiodonium, flavoprotein, macrophages, spin trapping, NADPH, superoxide dismutase
MeSH terms: Animals, Catalysis, Cyclic N-Oxides, Electron Spin Resonance Spectroscopy, Oxidoreductases, Oxygenases, Recombinant Proteins, Spin Labels, Superoxides, Nitric Oxide Synthase, Mice, Nitric Oxide Synthase Type II

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Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain

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