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Characterization of the Magnitude and Mechanism of Aldehyde Oxidase-mediated Nitric Oxide Production from Nitrite
Open accessAbstract
Aldehyde oxidase (AO) is a cytosolic enzyme with an important role in drug and xenobiotic metabolism. Although AO has structural similarity to bacterial nitrite reductases, it is unknown whether AO-catalyzed nitrite reduction can be an important source of NO. The mechanism, magnitude, and quantitative importance of AO-mediated nitrite reduction in tissues have not been reported. To investigate this pathway and its quantitative importance, EPR spectroscopy, chemiluminescence NO analyzer, and immunoassays of cGMP formation were performed. The kinetics and magnitude of AO-dependent NO formation were characterized. In the presence of typical aldehyde substrates or NADH, AO reduced nitrite to NO. Kinetics of AO-catalyzed nitrite reduction followed Michaelis-Menten kinetics under anaerobic conditions. Under physiological conditions, nitrite levels are far below its measured K(m) value in the presence of either the flavin site electron donor NADH or molybdenum site aldehyde electron donors. Under aerobic conditions with the FAD site-binding substrate, NADH, AO-mediated NO production was largely maintained, although with aldehyde substrates oxygen-dependent inhibition was seen. Oxygen tension, substrate, and pH levels were important regulators of AO-catalyzed NO generation. From kinetic data, it was determined that during ischemia hepatic, pulmonary, or myocardial AO and nitrite levels were sufficient to result in NO generation comparable to or exceeding maximal production by constitutive NO synthases. Thus, AO-catalyzed nitrite reduction can be an important source of NO generation, and its NO production will be further increased by therapeutic administration of nitrite.
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In the citing paper
“The mechanism of nitrite reduction by AO is similar to that of XOR where nitrite is reduced at the molybdenum site and either an aldehyde can supply electrons at that same site, or NADH can supply electrons from the flavin site [93].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [93]
In the citing paper
“Again, the low Km of AO for nitrite (about 3 mM) limits its NO production rate, but it has been estimated that AO mediated NO production from nitrite can reach 1.5 nM/s at low pH in the heart [93].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [93]
In the citing paper
“Since AO has a higher affinity for NADH than XOR, it is more likely to contribute to aerobic nitrite reduction than XOR with physiological levels of NADH [93].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [93]
In the citing paper
“Under aerobic conditions, the NADH-dependent process is favored as oxygen acts as a competitive inhibitor of nitrite reduction in the absence of NADH [93].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [93]
In the citing paper
“Like other nitrite reduction pathways, lowering pH increases the rate of AO-mediated reduction, but not as much as other pathways; about 35% in going from pH 7.4 to pH 6.0 [93].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [93]
In the citing paper
“Nitrite reduction is not exclusive to hemoglobin and myoglobin, with a variety of heme-containing and non-heme containing proteins including xanthine oxidoreductase [21, 22], aldehyde oxidase [62], neuroglobin [63, 64], eNOS [65], cytochrome c [47], carbonic anhydrase [66], cytochrome c oxidase [67], complex III [68], and cytochrome P450 [69] being suggested as mediators of NO-formation.”
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 [62]
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Metadata
- Authors
- Li, H., Kundu, T. K., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Li, Haitao
- Zweier, Jay L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 284
- Issue
- 49
- Pages
- 33850-33858
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2797155
- OpenAlex
- W2056934771
- Cited by
- 126
- References
- 49
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 8 · 2018: 13 · 2017: 9 · 2016: 7 · 2015: 13 · 2014: 15 · 2013: 12 · 2012: 9
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-38324, R01HL063744, HL 65608, P01HL065608, HL 63744, R01HL038324)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- aldehyde oxidase, nitric oxide production, nitrite reduction, nitrite, enzyme kinetics, Michaelis-Menten kinetics, NADH, oxygen inhibition, cyclic GMP, ischemia, nitrite therapy, nitrite reductase
- MeSH terms
- Animals, Electron Spin Resonance Spectroscopy, Flavins, Hydrogen-Ion Concentration, Immunoassay, Kinetics, Liver, Male, Molybdenum, Nitric Oxide, Nitrites, Xenobiotics, Rats, Sprague-Dawley, Aldehyde Oxidase, Rats
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