Identification of Amino Acid Substitutions that Confer a High Affinity for Sulfaphenazole Binding and a High Catalytic Efficiency for Warfarin Metabolism To P450 2C19

Human cytochrome P450s 2C9 and 2C19 metabolize many important drugs including tolbutamide, phenytoin, and (S)-warfarin. Although they differ at only 43 of 490 amino acids, sulfaphenazole (SFZ) is a potent and selective inhibitor of P450 2C9 with an IC50 and a spectrally determined binding constant,...

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Bibliographic Details
Published in:Biochemistry (Easton) 1998-11, Vol.37 (46), p.16270-16279
Main Authors: Jung, Frank, Griffin, Keith J, Song, Wu, Richardson, Toby H, Yang, Mierha, Johnson, Eric F
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution - genetics
Aryl Hydrocarbon Hydroxylases
Binding, Competitive - genetics
Catalysis
Cell Membrane - genetics
Cell Membrane - metabolism
Cytochrome P-450 CYP2C19
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Escherichia coli - genetics
Genetic Vectors - metabolism
Humans
Mixed Function Oxygenases - antagonists & inhibitors
Mixed Function Oxygenases - genetics
Mixed Function Oxygenases - metabolism
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - metabolism
Stereoisomerism
Sulfaphenazole - metabolism
Warfarin - chemistry
Warfarin - metabolism
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Summary:Human cytochrome P450s 2C9 and 2C19 metabolize many important drugs including tolbutamide, phenytoin, and (S)-warfarin. Although they differ at only 43 of 490 amino acids, sulfaphenazole (SFZ) is a potent and selective inhibitor of P450 2C9 with an IC50 and a spectrally determined binding constant, K S, of
ISSN:0006-2960
1520-4995
DOI:10.1021/bi981704c