Book chapter
Enzyme Kinetics, Inhibition, and Regioselectivity of Aldehyde Oxidase
Enzyme Kinetics in Drug Metabolism, pp.167-186
Methods in Molecular Biology, Humana Press
01/17/2014
Handle:
https://hdl.handle.net/2376/114475
PMID: 24523113
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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Details
- Title
- Enzyme Kinetics, Inhibition, and Regioselectivity of Aldehyde Oxidase
- Creators
- John T Barr - Department of Chemistry, Washington State University, Pullman, USAKanika Choughule - Department of Chemistry, Washington State University, Pullman, USAJeffrey P Jones - Department of Chemistry, Washington State University, Pullman, USA
- Publication Details
- Enzyme Kinetics in Drug Metabolism, pp.167-186
- Academic Unit
- Chemistry, Department of
- Series
- Methods in Molecular Biology
- Publisher
- Humana Press; Totowa, NJ
- Identifiers
- 99900548015401842
- Language
- English
- Resource Type
- Book chapter