Grover P Miller1. 1. University of Arkansas for Medical Sciences, Department of Biochemistry and Molecular Biology, 4301 W. Markham Street, Slot 516, Little Rock, AR 72205, USA. millergroverp@uams.edu
Abstract
BACKGROUND: Cytochrome P450 2E1 (CYP2E1) plays a central role in the metabolism and metabolic activation of a large number of small, mostly xenobiotic compounds. These qualities distinguish CYP2E1 from traditional enzymes and pose significant challenges to understanding the role and consequences of CYP2E1-mediated metabolism. OBJECTIVE: This review discusses recent advances in kinetic profiling, quantitative structure-activity relationships and structural studies that have furthered the development of tools to interpret and predict CYP2E1 metabolism. METHODS: Analysis of kinetic profiles by specific mechanisms produces important parameters describing specificity, stoichiometry and metabolism of molecules. Quantitative structure-activity relationships reveal a more specific basis for molecular recognition by CYP2E1. The corresponding protein structures imparting these interactions are the focus of chemical modifications, site-directed mutagenesis and homology modeling studies. RESULTS: Compilation of kinetic profiling for CYP2E1 substrates established the selectivity for small substrates, whose characteristics could be generalized in parameters for hydrophobicity and steric properties as determined by quantitative structure-activity relationships. The possibility of an effector site for monocyclic compounds added an interesting variable to these modeling efforts. Various structural studies identified important residues contributing to binding and catalysis as well as the volume and location of the active site relative to the heme moiety. Pressure and carbon monoxide-binding experiments also demonstrated the inherent conformational flexibility of CYP2E1 that may contribute to rate-limiting steps during catalytic turnover. CONCLUSION: Although combinations of these approaches have reinforced important observations, more work is needed to verify findings and seek broader impacts for various interpretative and predictive tools.
BACKGROUND:Cytochrome P450 2E1 (CYP2E1) plays a central role in the metabolism and metabolic activation of a large number of small, mostly xenobiotic compounds. These qualities distinguish CYP2E1 from traditional enzymes and pose significant challenges to understanding the role and consequences of CYP2E1-mediated metabolism. OBJECTIVE: This review discusses recent advances in kinetic profiling, quantitative structure-activity relationships and structural studies that have furthered the development of tools to interpret and predict CYP2E1 metabolism. METHODS: Analysis of kinetic profiles by specific mechanisms produces important parameters describing specificity, stoichiometry and metabolism of molecules. Quantitative structure-activity relationships reveal a more specific basis for molecular recognition by CYP2E1. The corresponding protein structures imparting these interactions are the focus of chemical modifications, site-directed mutagenesis and homology modeling studies. RESULTS: Compilation of kinetic profiling for CYP2E1 substrates established the selectivity for small substrates, whose characteristics could be generalized in parameters for hydrophobicity and steric properties as determined by quantitative structure-activity relationships. The possibility of an effector site for monocyclic compounds added an interesting variable to these modeling efforts. Various structural studies identified important residues contributing to binding and catalysis as well as the volume and location of the active site relative to the heme moiety. Pressure and carbon monoxide-binding experiments also demonstrated the inherent conformational flexibility of CYP2E1 that may contribute to rate-limiting steps during catalytic turnover. CONCLUSION: Although combinations of these approaches have reinforced important observations, more work is needed to verify findings and seek broader impacts for various interpretative and predictive tools.
Authors: Jessica H Hartman; Grover P Miller; Andres A Caro; Stephanie D Byrum; Lisa M Orr; Samuel G Mackintosh; Alan J Tackett; Lee Ann MacMillan-Crow; Lance M Hallberg; Bill T Ameredes; Gunnar Boysen Journal: Toxicology Date: 2017-01-09 Impact factor: 4.221
Authors: Jessica H Hartman; Lynda G Letzig; Dean W Roberts; Laura P James; E Kim Fifer; Grover P Miller Journal: Biochem Pharmacol Date: 2015-07-28 Impact factor: 5.858
Authors: Jessica H Hartman; Amber M Bradley; Ryan M Laddusaw; Martin D Perry; Grover P Miller Journal: Arch Biochem Biophys Date: 2013-06-27 Impact factor: 4.013