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Research ArticleArticle

Site-Directed Mutagenesis at the Molybdenum Pterin Cofactor Site of the Human Aldehyde Oxidase: Interrogating the Kinetic Differences Between Human and Cynomolgus Monkey

Armina Abbasi, Carolyn A. Joswig-Jones and Jeffrey P. Jones
Drug Metabolism and Disposition December 2020, 48 (12) 1364-1371; DOI: https://doi.org/10.1124/dmd.120.000187
Armina Abbasi
Department of Chemistry, Washington State University, Pullman, Washington
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Carolyn A. Joswig-Jones
Department of Chemistry, Washington State University, Pullman, Washington
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Jeffrey P. Jones
Department of Chemistry, Washington State University, Pullman, Washington
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Abstract

The estimation of the drug clearance by aldehyde oxidase (AO) has been complicated because of this enzyme’s atypical kinetics and species and substrate specificity. Since human AO (hAO) and cynomolgus monkey AO (mAO) have a 95.1% sequence identity, cynomolgus monkeys may be the best species for estimating AO clearance in humans. Here, O6-benzylguanine (O6BG) and dantrolene were used under anaerobic conditions, as oxidative and reductive substrates of AO, respectively, to compare and contrast the kinetics of these two species through numerical modeling. Whereas dantrolene reduction followed the same linear kinetics in both species, the oxidation rate of O6BG was also linear in mAO and did not follow the already established biphasic kinetics of hAO. In an attempt to determine why hAO and mAO are kinetically distinct, we have altered the hAO V811 and F885 amino acids at the oxidation site adjacent to the molybdenum pterin cofactor to the corresponding alanine and leucine in mAO, respectively. Although some shift to a more monkey-like kinetics was observed for the V811A mutant, five more mutations around the AO cofactors still need to be investigated for this purpose. In comparing the oxidative and reductive rates of metabolism under anaerobic conditions, we have come to the conclusion that despite having similar rates of reduction (4-fold difference), the oxidation rate in mAO is more than 50-fold slower than hAO. This finding implies that the presence of nonlinearity in AO kinetics is dependent upon the degree of imbalance between the rates of oxidation and reduction in this enzyme.

SIGNIFICANCE STATEMENT Although they have as much as 95.1% sequence identity, human and cynomolgus monkey aldehyde oxidase are kinetically distinct. Therefore, monkeys may not be good estimators of drug clearance in humans.

Footnotes

    • Received July 17, 2020.
    • Accepted September 25, 2020.
  • This work was supported by National Institutes of Health National Institute of General Medical Sciences [GM100874].

  • https://doi.org/10.1124/dmd.120.000187.

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

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (12)
Drug Metabolism and Disposition
Vol. 48, Issue 12
1 Dec 2020
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Research ArticleArticle

Kinetic Differences Between Human and Cynomolgus Monkey Aldehyde Oxidase

Armina Abbasi, Carolyn A. Joswig-Jones and Jeffrey P. Jones
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1364-1371; DOI: https://doi.org/10.1124/dmd.120.000187

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Research ArticleArticle

Kinetic Differences Between Human and Cynomolgus Monkey Aldehyde Oxidase

Armina Abbasi, Carolyn A. Joswig-Jones and Jeffrey P. Jones
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1364-1371; DOI: https://doi.org/10.1124/dmd.120.000187
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