MOLECULAR MODELING OF HUMAN CYP2C SUBFAMILY ENZYMES CYP2C9 AND CYP2C19 - RATIONALIZATION OF SUBSTRATE-SPECIFICITY AND SITE-DIRECTED MUTAGENESIS EXPERIMENTS IN THE CYP2C SUBFAMILY

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-dimensional structures of the CYP2 C enzymes are consistent with known experimental evidence from site-di rected mutagenesis, antibody recognition and regiospecificity of subst rate metabolism. 3. The variations in substrate specificity between CY P2C9 and CYP2C19 can be rationalized in terms of single amino acid res idue changes within the putative active site region, of which I99H app ears to be the most significant.