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Cited by 26Pharmacogenetics and Drug MetabolismMetal-Catalyzed Oxygenation MechanismsRedox biology and oxidative stress

A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase

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Foti, Alessandro, Dorendorf, Frank, Leimkühler, Silke·2017·PLOS ONE
DOI 10.1371/journal.pone.0182061PMC PMC5531472
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Abstract

Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. The physiological function of mammalian AOX isoenzymes is still unclear, however, human AOX (hAOX1) is an emerging enzyme in phase-I drug metabolism. Indeed, the number of xenobiotics acting as hAOX1 substrates is increasing. Further, numerous single-nucleotide polymorphisms (SNPs) have been identified within the hAOX1 gene. SNPs are a major source of inter-individual variability in the human population, and SNP-based amino acid exchanges in hAOX1 reportedly modulate the catalytic function of the enzyme in either a positive or negative fashion. In this report we selected ten novel SNPs resulting in amino acid exchanges in proximity to the FAD site of hAOX1 and characterized the purified enzymes after heterologous expression in Escherichia coli. The hAOX1 variants were characterized carefully by quantitative differences in their ability to produce superoxide radical. ROS represent prominent key molecules in physiological and pathological conditions in the cell. Our data reveal significant alterations in superoxide anion production among the variants. In particular the SNP-based amino acid exchange L438V in proximity to the isoalloxanzine ring of the FAD cofactor resulted in increased rate of superoxide radical production of 75%. Considering the high toxicity of the superoxide in the cell, the hAOX1-L438V SNP variant is an eventual candidate for critical or pathological roles of this natural variant within the human population.

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  • A known single nucleotide polymorphism in the AOX1 gene produces a mutant enzyme with increased superoxide formation rates in vitro.

    “However, a known single nucleotide polymorphism in the AOX1 gene was shown to produce a mutant enzyme with increased superoxide formation rates in vitro (304).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [304]

  • The human AOX1 isoform is not reactive toward NADH.

    “Recent work on the human enzyme shows that the production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes, and the enzyme is not reactive toward NADH (304).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [304]

  • The production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes.

    “Recent work on the human enzyme shows that the production of superoxide by the human AOX1 isoform is lower than that of the rat enzymes, and the enzyme is not reactive toward NADH (304).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [304]

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Research works printed but not linked: 2

  1. [7]Garattini E, Fratelli M, Terao M (2008) Mammalian aldehyde oxidases: genetics, evolution and biochemistry. Cellular and molecular life sciences 65: 1019– 1048. doi: 10.1007/s00018-007-7398-y 18066686 PMC11131919 · DOI
  2. [21]Kundu TK, Hille R, Velayutham M, Zweier JL (2007) Characterization of superoxide production from aldehyde oxidase: an important source of oxidants in biological tissues. Arch Biochem Biophys 460: 113– 121. doi: 10.1016/j.abb.2006.12.032 17353002 PMC4073616 · DOI · Paper page

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Authors
Foti, A., Dorendorf, F., & Leimkühler, S.
Affiliations
University of Potsdam (DE)
Corresponding author
Leimkühler, Silke
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2017-07-27
Volume
12
Issue
7
Pages
e0182061
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0182061
PMC
PMC5531472
OpenAlex
W2739900731
Cited by
26
References
30
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 1 · 2019: 7 · 2018: 2
FWCI
2.91
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • publish.UP (University of Potsdam) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft (Le1171/8)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
single nucleotide polymorphisms, reactive oxygen species, FAD cofactor, molybdenum enzymes, phase I metabolism, interindividual variability, heterologous expression, isoalloxazine ring
MeSH terms
Amino Acids, Anaerobiosis, Coenzymes, Electron Transport, Flavin-Adenine Dinucleotide, Humans, Iron, Kinetics, Models, Molecular, Molybdenum, NAD, Onium Compounds, Spectrophotometry, Ultraviolet, Superoxides, Reactive Oxygen Species, Catalytic Domain, Polymorphism, Single Nucleotide, Aldehyde Oxidase, Mutant Proteins, Protein Multimerization

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