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Research ArticleArticle

Direct Comparison of the Enzymatic Characteristics and Superoxide Production of the Four Aldehyde Oxidase Enzymes Present in Mouse

Gökhan Kücükgöze, Mineko Terao, Enrico Garattini and Silke Leimkühler
Drug Metabolism and Disposition August 2017, 45 (8) 947-955; DOI: https://doi.org/10.1124/dmd.117.075937
Gökhan Kücükgöze
Institut für Biochemie and Biologie, Universität Potsdam, Potsdam, Germany (G.K., S.L.); Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy (M.T., E.G.)
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Mineko Terao
Institut für Biochemie and Biologie, Universität Potsdam, Potsdam, Germany (G.K., S.L.); Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy (M.T., E.G.)
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Enrico Garattini
Institut für Biochemie and Biologie, Universität Potsdam, Potsdam, Germany (G.K., S.L.); Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy (M.T., E.G.)
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Silke Leimkühler
Institut für Biochemie and Biologie, Universität Potsdam, Potsdam, Germany (G.K., S.L.); Laboratory of Molecular Biology, Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy (M.T., E.G.)
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Abstract

Aldehyde oxidases (AOXs) are molybdoflavoenzymes with an important role in the metabolism and detoxification of heterocyclic compounds and aliphatic as well as aromatic aldehydes. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. Four different enzymes, mAOX1, mAOX3, mAOX4, and mAOX2, which are the products of distinct genes, are present in the mouse. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes has never been performed. In this report, the four catalytically active mAOX enzymes were purified after heterologous expression in Escherichia coli. The kinetic parameters of the four mouse AOX enzymes were determined and compared with the use of six predicted substrates of physiologic and toxicological interest, i.e., retinaldehyde, N1-methylnicotinamide, pyridoxal, vanillin, 4-(dimethylamino)cinnamaldehyde (p-DMAC), and salicylaldehyde. While retinaldehyde, vanillin, p-DMAC, and salycilaldehyde are efficient substrates for the four mouse AOX enzymes, N1-methylnicotinamide is not a substrate of mAOX1 or mAOX4, and pyridoxal is not metabolized by any of the purified enzymes. Overall, mAOX1, mAOX2, mAOX3, and mAOX4 are characterized by significantly different KM and kcat values for the active substrates. The four mouse AOXs are also characterized by quantitative differences in their ability to produce superoxide radicals. With respect to this last point, mAOX2 is the enzyme generating the largest rate of superoxide radicals of around 40% in relation to moles of substrate converted, and mAOX1, the homolog to the human enzyme, produces a rate of approximately 30% of superoxide radicals with the same substrate.

Footnotes

    • Received March 13, 2017.
    • Accepted May 15, 2017.
  • This work was supported by the Deutsche Forschungsgemeinschaft [LE1171/8-1] and a fellowship from the University of Potsdam.

  • https://doi.org.org/10.1124/dmd.117.075937.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (8)
Drug Metabolism and Disposition
Vol. 45, Issue 8
1 Aug 2017
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Research ArticleArticle

Characterization of Aldehyde Oxidase Enzymes from Mouse

Gökhan Kücükgöze, Mineko Terao, Enrico Garattini and Silke Leimkühler
Drug Metabolism and Disposition August 1, 2017, 45 (8) 947-955; DOI: https://doi.org/10.1124/dmd.117.075937

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Research ArticleArticle

Characterization of Aldehyde Oxidase Enzymes from Mouse

Gökhan Kücükgöze, Mineko Terao, Enrico Garattini and Silke Leimkühler
Drug Metabolism and Disposition August 1, 2017, 45 (8) 947-955; DOI: https://doi.org/10.1124/dmd.117.075937
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