Functional analysis of phenylalanine residues in the active site of cytochrome P450 2C9.

ABSTRACT: The two published crystal structures of cytochrome P450 2C9, complexed with ( S)-warfarin or flurbiprofen, implicate a cluster of three active site phenylalanine residues (F100, F114, F476) in ligand binding. However, these three residues appear to interact differently with these two ligands based on the static crystal structures. To elucidate the importance of CYP2C9's active site phenylalanines on substrate binding, orientation, and catalytic turnover, a series of leucine and tryptophan mutants were constructed and their interactions with ( S)-warfarin and ( S)-flurbiprofen examined. The F100-->L mutation had minor effects on substrate binding and metabolism of each substrate. In contrast, the F114L and F476L mutants exhibited substantially reduced ( S)-warfarin metabolism and altered hy

SUBMITTER: Mosher CM 

PROVIDER: S-EPMC2713172 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature