MOLECULAR MODELING OF CYTOCHROME P4502D6 (CYP2D6) BASED ON AN ALIGNMENT WITH CYP102 - STRUCTURAL STUDIES ON SPECIFIC CYP2D6 SUBSTRATE METABOLISM

1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the speci fic inhibitor quinidine. 3. Some of the allelic variants in CYP2D6, wh ich give rise to genetic polymorphisms in 2D6-mediated metabolism, can be rationalized in terms of their position within the active site reg ion. 4. The results of site-directed mutagenesis experiments are consi stent with the CYP2D6 model generated from the CYP102 crystal structur e. 5. The possibility of an alternative orientation within the active sire may explain the CYP2D6-mediated metabolism of relatively large si zed substrates.