Investigating human P450s involved in drug metabolism via homology with high-resolution P450 crystal structures of the CYP2C subfamily.
The important role of high-resolution crystal structures of cytochrome P450 (CYP) enzymes for the generation of P450 models by homology is discussed. The main focus is on human P450 enzymes involved in drug metabolism, where the role of homology modelling has been emphasized in the recent literature. Report of the first human P450 crystal structure has provided an opportunity for comparison between those modelled from other crystallographic templates, and the recent substrate-bound rabbit CYP2C5 structure exemplifies the relevance of high-resolution template structures to generating 3-D models of P450s where the homology is relatively high. In particular, the homology models of human CYP1 and CYP2 family enzymes are presented, where good agreement with experiment findings are apparent.
Lewis
David F V
DF
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. d.lewis@surrey.ac.uk
Ito
Yuko
Y
Goldfarb
Peter S
PS
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000502:physiology; D000072467:Cytochrome P450 Family 2; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry; D008958:Models, Molecular; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D013255:Steroid 21-Hydroxylase / Q000737:chemistry*
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; C065407:CYP2C5 protein, Oryctolagus cuniculus; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; D010089:Oxidoreductases, N-Demethylating