Characterization of the Magnitude and Kinetics of Xanthine Oxidase-catalyzed Nitrite Reduction
Open accessAbstract
Xanthine oxidase (XO)-catalyzed nitrite reduction with nitric oxide (NO) production has been reported to occur under anaerobic conditions, but questions remain regarding the magnitude, kinetics, and biological importance of this process. To characterize this mechanism and its quantitative importance in biological systems, electron paramagnetic resonance spectroscopy, chemiluminescence NO analyzer, and NO electrode studies were performed. The XO reducing substrates xanthine, NADH, and 2,3-dihydroxybenz-aldehyde triggered nitrite reduction to NO, and the molybdenum-binding XO inhibitor oxypurinol inhibited this NO formation, indicating that nitrite reduction occurs at the molybdenum site. However, at higher xanthine concentrations, partial inhibition was seen, suggesting the formation of a substrate-bound reduced enzyme complex with xanthine blocking the molybdenum site. Studies of the pH dependence of NO formation indicated that XO-mediated nitrite reduction occurred via an acid-catalyzed mechanism. Nitrite and reducing substrate concentrations were important regulators of XO-catalyzed NO generation. The substrate dependence of anaerobic XO-catalyzed nitrite reduction followed Michaelis-Menten kinetics, enabling prediction of the magnitude of NO formation and delineation of the quantitative importance of this process in biological systems. It was determined that under conditions occurring during no-flow ischemia, myocardial XO and nitrite levels are sufficient to generate NO levels comparable to those produced from nitric oxide synthase. Thus, XO-catalyzed nitrite reduction can be an important source of NO generation under ischemic conditions.
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To date, XO is the most relevant nonheme nitrite reductase in vivo.
“To date, XO is the most relevant nonheme nitrite reductase in vivo. Many studies have shown the relevance of XO in mammalian physiology (357, 568, 577, 578, 998).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [577]
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 [86]
Nitrite-mediated cytoprotection is mediated by NO production from the molybdenum-containing enzyme XOR and to some extent SO.
“Numerous studies have suggested that nitrite-mediated cytoprotection is mediated by NO production from the molybdenum containing enzyme XOR [8, 39, 86, 118, 127] and to some extent SO [39] as well.”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [86]
XOR-mediated NO generation from nitrite is sufficient in conditions mimicking those of the ischemic heart.
“The Zweier group demonstrated the sufficiency of XOR mediated NO generation from nitrite in conditions mimicking those of the ischemic heart [86].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [86]
Animals do not encode a classical nitrate reductase, although bovine xanthine oxidase can reduce nitrate into nitrite.
“Eukaryotic nitrate reductase (eukNR) has been isolated from plants and fungi; animals do not encode a classical nitrate reductase, although bovine xanthine oxidase (XO) can reduce nitrate into nitrite.”
From Nitrate and periplasmic nitrate reductases (2014) · cites this paper as [79]
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 [71]
For xanthine oxidoreductase, the KM for nitrite binding to the molybdenum site is approximately 2.5 mM, two or three orders of magnitude higher than normal tissue levels.
“the KM for nitrite binding to the molybdenum site is approximately 2.5mM, two or three orders of magnitude higher than normal tissue levels[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 [71]
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- Authors
- Li, H., Samouilov, A., Liu, X., & Zweier, J. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Zweier, Jay L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 276
- Issue
- 27
- Pages
- 24482-24489
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2052327619
- Cited by
- 280
- References
- 32
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 10 · 2022: 5 · 2021: 8 · 2020: 7 · 2019: 9 · 2018: 12 · 2017: 11 · 2016: 3 · 2015: 13 · 2014: 18 · 2013: 18 · 2012: 13
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- 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, nitrite reduction, nitric oxide production, xanthine, NADH, 2,3-dihydroxybenzaldehyde, Michaelis-Menten kinetics, pH dependence, substrate inhibition, myocardial ischemia, nitric oxide synthase
- MeSH terms
- Catalysis, Electrochemistry, Electron Spin Resonance Spectroscopy, Hydrogen-Ion Concentration, Kinetics, Luminescent Measurements, Molybdenum, Nitric Oxide, Nitrites, Oxidation-Reduction, Oxygen, Xanthine Oxidase
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