Molecular modelling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed mutagenesis experiments in the CYP2C subfamily

• Published in: Xenobiotica 1998-03, Vol.28 (3), p.235-268
• Main Authors: LEWIS, D. F. V., DICKINS, M., WEAVER, R. J., EDDERSHAW, P. J., GOLDFARB, P. S., TARBIT, M. H.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Isoenzymes - chemistry; Isoenzymes - genetics; Isoenzymes - metabolism; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Oxidoreductases; Sequence Alignment; Species Specificity; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases - chemistry; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Substrate Specificity
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/004982598239542

1. The results of molecular modelling of human CYP2C isozymes, CYP2C9 and CYP2C19, are reported based on an alignment with a bacterial form of the enzyme, CYP102. 2. The three-dimensionalstructures of the CYP2C enzymes are consistent with known experimental evidence from site-directed mutagenesis, antibody recognition and regiospecificity of substrate metabolism. 3. The variations in substrate specificity between CYP2C9 and CYP2C19 can be rationalized in terms of single amino acid residue changes within the putative active site region, of which I99H appears to be the most significant.