Characterization of the effects of oxygen on xanthine oxidase-mediated nitric oxide formation
Open accessAbstract
Under anaerobic conditions, xanthine oxidase (XO)-catalyzed nitrite reduction can be an important source of nitric oxide (NO). However, questions remain regarding whether significant XO-mediated NO generation also occurs under aerobic conditions. Therefore, electron paramagnetic resonance, chemiluminescence NO-analyzer, and NO-electrode studies were performed to characterize the kinetics and magnitude of XO-mediated nitrite reduction as a function of oxygen tension. With substrates xanthine or 2,3-dihydroxybenz-aldehyde that provide electrons to XO at the molybdenum site, the rate of NO production followed Michaelis-Menten kinetics, and oxygen functioned as a competitive inhibitor of nitrite reduction. However, with flavin-adenine dinucleotide site-binding substrate NADH as electron donor, aerobic NO production was maintained at more than 70% of anaerobic levels, and binding of NADH to the flavin-adenine dinucleotide site seemed to prevent oxygen binding. Therefore, under aerobic conditions, NADH would be the main electron donor for XO-catalyzed NO production in tissues. Studies of the pH dependence of NO formation indicated that lower pH values decrease oxygen reduction but greatly increase nitrite reduction, facilitating NO generation. Isotope tracer studies demonstrated that XO-mediated NO formation occurs in normoxic and hypoxic heart tissue. Thus, XO-mediated NO generation occurs under aerobic conditions and is regulated by oxygen tension, pH, nitrite, and reducing substrate concentrations.
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Process I involves molybdenum reduction by xanthine or 2,3-dihydroxybenz-aldehyde.
“Process I involves molybdenum reduction by xanthine or 2,3-dihydroxybenz-aldehyde [87].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
In Process I, the FAD site is open and oxygen competes with nitrite for electrons so that process 1 is favored in hypoxia and anoxia.
“In this process, the FAD site is open and oxygen competes with nitrite for electrons so that process 1 is favored in hypoxia and anoxia (Figure 5).”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
In Process II, NADH occupies the FAD site so oxygen no longer competes with nitrite for electrons; Process II is independent of oxygen tension.
“In Process II, NADH occupies the FAD site so oxygen no longer competes with nitrite for electrons [87]. Process II is then independent of oxygen tension (Figure 5).”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
Nitrite is reduced by the molybdenum of XOR which can itself be reduced by one of two pathways so that overall nitrite reduction has been described as occurring by two separate processes.
“Nitrite is reduced by the molybdenum which can itself be reduced by one of two pathways so that overall nitrite reduction has been described as occurring by two separate processes [87].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
The Vmax of XOR is constant over different oxygen tensions and equal to about 10 nM/mg protein/s.
“The Vmax is constant over different oxygen tensions and equal to about 10 nM/mg protein/s [87].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
The Michaelis constant Km for XOR has been reported to be 2.5 mM under some conditions and 12 mM to 59 mM with oxygen tensions of 2% to 21%.
“The Michaelis constant Km has been reported to be 2.5 mM under some conditions [86]. and 12 mM to 59 mM with oxygen tensions of 2% to 21% [87].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [87]
The nitrite reductase activity of neuroglobin or cytochrome c is negligible when the heme is hexacoordinated.
“the nitrite reductase activity of neuroglobin [63, 64, 70, 76] or cytochrome c [47] is negligible when the heme is hexacoordinated.”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [70]
Xanthine oxidase dependent reduction of nitrite requires substantial hypoxia or anoxia, or high concentrations of SOD to prevent NO scavenging by superoxide.
“xanthine oxidase dependent reduction of nitrite requires substantial hypoxia (or anoxia) or the presence of high concentrations of SOD to prevent NO scavenging by superoxide produced via oxygen reduction catalyzed by the same xanthine oxidoreductase [70, 71].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [70]
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References 40 · Cited by 146
Research works printed but not linked: 4
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- Authors
- Li, H., Samouilov, A., Liu, X., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Zweier, Jay L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 279
- Issue
- 17
- Pages
- 16939-16946
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1986703419
- Cited by
- 146
- References
- 40
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 1 · 2019: 3 · 2018: 6 · 2017: 11 · 2016: 5 · 2015: 7 · 2014: 7 · 2013: 10 · 2012: 8
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL38324, HL65608)
- National Heart, Lung, and Blood Institute (HL-38324, R01HL063744, HL 65608, P01HL065608, HL 63744)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- xanthine oxidase, nitric oxide production, nitrite reduction, oxygen partial pressure, aerobic conditions, competitive inhibition, pH dependence, isotope tracers, myocardium, hypoxia, Michaelis-Menten kinetics
- MeSH terms
- Animals, Benzaldehydes, Binding Sites, Binding, Competitive, Biochemistry, Catechols, Dose-Response Relationship, Drug, Electrochemistry, Electrodes, Electron Spin Resonance Spectroscopy, Electrons, Flavins, Hydrogen-Ion Concentration, Kinetics, Luminescent Measurements, Magnetics, Male, Models, Chemical, Molybdenum, Myocardium, Nitric Oxide, Oxygen, Protein Binding, Time Factors, Xanthine Oxidase, Rats, Sprague-Dawley, Cultured Milk Products, Rats
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