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Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain
Open accessAbstract
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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“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]
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“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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Metadata
- 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.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-08
- Volume
- 273
- Issue
- 35
- Pages
- 22635-22639
- ISSN
- 0021-9258 (ISSN-L)
- 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
- 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 (medical) › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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