Dissertation
NUMERICAL MODELING OF THE KINETICS OF ALDEHYDE OXIDASE: ENTERING A NEW KINETIC ERA
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/111685
Abstract
Aldehyde oxidase (AO) is an enzyme of emerging importance in the field of drug metabolism. However, AO has proven to have kinetic complexities owing to its substrate and species specificity. Most traditional methods used in drug development process such as in vitro- in vivo extrapolation or allometric scaling seem to lead to an underestimation of AO clearance in human. This work focuses on AO complexities and the implementation of novel numerical modeling techniques to better understand the kinetics of this enzyme. After a brief introduction to the scope of this work in chapter one, chapter two features the advantages of using numerical modeling in studying the nonlinear kinetics of AO. It was found that this nonlinearity in the progress curve for five different substrates of this enzyme-O6-benzylguanine, N-(2-dimethylamino)ethyl)-acridine-3-carboxamide, zaleplon, phthalazine, and BIBX1382 [N8-(3-chloro-4-fluorophenyl)-N2-(1-methyl-4-piperidinyl)-pyrimido[5,4,-d]pyrimidine-2,8-diamine dihydrochloride]-is due to the slow rate of oxygen reduction rather than substrate depletion or enzyme inactivation through reactive oxygen species as it was speculated before. Chapter three goes over the kinetic differences between human and cynomolgus monkey AO, a potential surrogate for human, and the molecular basis of these differences. Despite having 95.1% AO sequence identity, these two species show very distinct kinetic behavior with human having nonlinear and cynomolgus monkey displaying linear oxidation rates. Lastly, 3D Kinetics as a novel kinetic platform is presented in chapter four. This type of analysis goes beyond the kinetics of AO. The goal of this chapter is to combine the simplicity of Michaelis-Menten kinetics with the flexibility of numerical modeling for analyzing different enzymatic systems.
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Details
- Title
- NUMERICAL MODELING OF THE KINETICS OF ALDEHYDE OXIDASE: ENTERING A NEW KINETIC ERA
- Creators
- Armina Abbasi
- Contributors
- Jeffrey P. Jones (Advisor)ChulHee Kang (Committee Member)Clifford E. Berkman (Committee Member)Gregory J. Crouch (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Chemistry, Department of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 148
- Identifiers
- 99900581609601842
- Language
- English
- Resource Type
- Dissertation