Molecular modelling of the human cytochrome P450 isoform CYP2A6 and investigations of CYP2A substrate selectivity.
(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.
Lewis
D F
DF
School of Biological Sciences, University of Surrey, Guildford, UK.
Dickins
M
M
Lake
B G
BG
Eddershaw
P J
PJ
Tarbit
M H
MH
Goldfarb
P S
PS
D000595:Amino Acid Sequence; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003374:Coumarins / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D017316:Fadrozole / Q000378:metabolism; D005663:Furans / Q000378:metabolism; D006801:Humans; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; C065427:losigame; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D017316:Fadrozole