The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
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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Nitric oxide: physiology, pathophysiology, and pharmacology.
Moncada, S., Palmer, R. M., & Higgs, E. A. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06663-3 · Cited by 15,525
Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., & Freeman, B. A. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.4.1620 · Cited by 7,029
Nitric oxide synthases: Roles, tolls, and controls
Nathan, C., & Xie, Q. W. (1994) · Cell · doi:10.1016/0092-8674(94)90266-6 · Cited by 2,920
Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase
Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C. J., Reed, R. R., & Snyder, S. H. (1991) · Nature · doi:10.1038/351714a0 · Cited by 2,354
Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.
Bredt, D. S., & Snyder, S. H. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.9030 · Cited by 1,849
Nitric oxide synthase structure and mechanism
Marletta, M. A. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)31375-9 · Cited by 1,338
Nitric Oxide Synthases: Properties and Catalytic Mechanism
Griffith, O. W., & Stuehr, D. J. (1995) · Annual Review of Physiology · doi:10.1146/annurev.ph.57.030195.003423 · Cited by 1,311
Generation of superoxide by purified brain nitric oxide synthase
Pou, S., Pou, W. S., Bredt, D. S., Snyder, S. H., & Rosen, G. M. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)35745-4 · Cited by 750
Xia, Y., Dawson, V. L., Dawson, T. M., Snyder, S. H., & Zweier, J. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6770 · Cited by 717
Self-citationSuperoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages
Xia, Y., & Zweier, J. L. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.13.6954 · Cited by 691
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- Moncada, 1991, Pharmacol. Rev., 43, 109
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Nitric oxide synthases: structure, function and inhibition
ALDERTON, W. K., COOPER, C. E., & KNOWLES, R. G. (2001) · Biochemical Journal · doi:10.1042/bj3570593 · Cited by 4,110
The metabolic signature of macrophage responses
Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01462 · Cited by 2,021
Reactive Oxygen Species in Metabolic and Inflammatory Signaling
Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018) · Circulation Research · doi:10.1161/circresaha.117.311401 · Cited by 2,081
Regulation of immune responses by L-arginine metabolism
Bronte, V., & Zanovello, P. (2005) · Nature Reviews Immunology · doi:10.1038/nri1668 · Cited by 1,775
Oxygen, oxidative stress, hypoxia, and heart failure
Giordano, F. J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24408 · Cited by 1,515
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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