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Enzyme Kinetics, Inhibition, and Regioselectivity of Aldehyde Oxidase

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Enzyme Kinetics in Drug Metabolism

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1113))

Abstract

The aldehyde oxidase (AO) enzyme family plays an increasing role in drug development. However, a number of compounds that are AO substrates have failed in the clinic because the clearance or toxicity is underestimated by preclinical species. Human AO is much more active than rodent AO, and dogs do not have functional AO. While AOs normally make non-reactive metabolites such as lactams, the metabolic products often have much lower solubility that can lead to renal failure. While an endogenous substrate for the oxidation reaction is not known, electron acceptors for the reductive part of the reaction include oxygen and nitrites. Reduction of oxygen leads to the reactive oxygen species (ROS) superoxide radical anion, and hydrogen peroxide. Reduction of nitrite leads to the formation of nitric oxide with potential pharmacological implications. To date, no clinically important drug–drug interactions (DDIs) have been observed for AOs. However, the inhibition kinetics are complex, and multiple probe substrates should be used when assessing the potential for DDIs. Finally, AO appears to be amenable to computational predictions of both regioselectivity and rates of reaction, which holds promise for virtual screening.

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Authors and Affiliations

  1. Department of Chemistry, Washington State University, Pullman, WA, USA

    John T. Barr, Kanika Choughule & Jeffrey P. Jones

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  1. John T. Barr
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  2. Kanika Choughule
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  3. Jeffrey P. Jones
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Editors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA

    Swati Nagar

  2. Novartis Inst. for BioMedical Research, Cambridge, Massachusetts, USA

    Upendra A. Argikar

  3. Drug Metabolism, Boehringer Ingelheim, Ridgefield, Connecticut, USA

    Donald J. Tweedie

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Barr, J.T., Choughule, K., Jones, J.P. (2014). Enzyme Kinetics, Inhibition, and Regioselectivity of Aldehyde Oxidase. In: Nagar, S., Argikar, U., Tweedie, D. (eds) Enzyme Kinetics in Drug Metabolism. Methods in Molecular Biology, vol 1113. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-758-7_9

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  • DOI: https://doi.org/10.1007/978-1-62703-758-7_9

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