Aldehyde Oxidase Functions as a Superoxide Generating NADH Oxidase: An Important Redox Regulated Pathway of Cellular Oxygen Radical Formation
Open accessAbstract
The enzyme aldehyde oxidase (AO) is a member of the molybdenum hydroxylase family that includes xanthine oxidoreductase (XOR); however, its physiological substrates and functions remain unclear. Moreover, little is known about its role in cellular redox stress. Utilizing electron paramagnetic resonance spin trapping, we measured the role of AO in the generation of reactive oxygen species (ROS) through the oxidation of NADH and the effects of inhibitors of AO on NADH-mediated superoxide (O(2)(•−)) generation. NADH was found to be a good substrate for AO with apparent K(m) and V(max) values of 29 μM and 12 nmol min(-1) mg(-1), respectively. From O(2)(•−) generation measurements by cytochrome c reduction the apparent K(m) and V(max) values of NADH for AO were 11 μM and 15 nmol min(-1) mg(-1), respectively. With NADH oxidation by AO, ≥65% of the total electron flux led to O(2)(•−) generation. Diphenyleneiodonium completely inhibited AO-mediated O(2)(•−) production, confirming that this occurs at the FAD site. Inhibitors of this NADH-derived O(2)(•−) generation were studied with amidone the most potent exerting complete inhibition at 100 μM concentration, while 150 μM menadione, raloxifene, or β-estradiol led to 81%, 46%, or 26% inhibition, respectively. From the kinetic data, and the levels of AO and NADH, O(2)(•−) production was estimated to be ~89 and ~4 nM/s in liver and heart, respectively, much higher than that estimated for XOR under similar conditions. Owing to the ubiquitous distribution of NADH, aldehydes, and other endogenous AO substrates, AO is predicted to have an important role in cellular redox stress and related disease pathogenesis.
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The Mo-containing protein AO has been described as a potential source of superoxide in vivo.
“The Mo-containing protein AO has also been described as a potential source of superoxide in vivo (538, 539).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [538]
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- Authors
- Kundu, T. K., Velayutham, M., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Zweier, Jay L.
- ORCID
- Zweier, Jay L.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-03-19
- Volume
- 51
- Issue
- 13
- Pages
- 2930-2939
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC3954720
- OpenAlex
- W2092178799
- Cited by
- 93
- References
- 57
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 1 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 17 · 2013: 4 · 2012: 2
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-38324, R01HL063744, HL 65608, P01HL065608, HL 63744, R01HL038324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- aldehyde oxidase, superoxide production, NADH oxidation, reactive oxygen species, molybdenum hydroxylases, xanthine oxidoreductase, redox stress, diphenyleneiodonium, menadione, raloxifene, beta-estradiol, enzyme kinetics, liver, heart
- MeSH terms
- Electron Spin Resonance Spectroscopy, Kinetics, Multienzyme Complexes, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Superoxides, Aldehyde Oxidase
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