Abstract
(1) The generation of a homology model of CYP2A6, the major catalyst of human hepatic coumarin 7-hydroxylase activity, involves the use of the recently published substrate-bound CYP102 crystal structure as a template. (2) A substantial number of structurally diverse CYP2A6 substrates are found to dock satisfactorily within the putative active site of the enzyme, leading to the formulation of a structural template (or pharmacophore) for CYP2A6 specificity/selectivity. (3) The CYP2A6 model is consistent with available evidence from site-directed mutagenesis studies carried out on CYP2A subfamily isoforms, and enables some explanation of species differences in CYP2A-mediated metabolism of certain substrates. (4) Quantitative structure-activity relationship (QSAR) analysis of CYP2A5 (the mouse orthologue) mutants yields statistically significant correlations between various properties of amino acid residues and coumarin 7-hydroxylase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Aryl Hydrocarbon Hydroxylases*
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Coumarins / metabolism
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Cytochrome P-450 CYP2A6
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / chemistry*
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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Cytochrome P450 Family 2
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Fadrozole / metabolism
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Furans / metabolism
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Humans
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Mice
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Mixed Function Oxygenases / antagonists & inhibitors
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Mixed Function Oxygenases / chemistry*
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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Models, Molecular*
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Molecular Sequence Data
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Coumarins
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Cytochrome P-450 Enzyme Inhibitors
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Furans
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losigame
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Cytochrome P-450 Enzyme System
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coumarin
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Mixed Function Oxygenases
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Aryl Hydrocarbon Hydroxylases
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CYP2A6 protein, human
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Cyp2a5 protein, mouse
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Cytochrome P-450 CYP2A6
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Cytochrome P450 Family 2
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Fadrozole