Homology modelling of human CYP2 family enzymes based on the CYP2C5 crystal structure.
1. The construction of molecular models for human cytochromes P450 from the CYP2 family are reported, utilizing the recently available crystal structure of CYP2C5, which is also a mammalian (rabbit) form of the enzyme. 2. In particular, selective substrate interactions with CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 are described in the context of favourable contacts with active site amino acid residues that appear to orientate each substrate for metabolism at the experimentally observed position. 3. The results are consistent with reported findings from site-directed mutagenesis experiments with the CYP2 family, and with published information on substrate metabolism.
Lewis
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Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK. d.lewis@surrey.ac.uk
D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases; D018360:Crystallography, X-Ray; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase / Q000737:chemistry*; D013250:Steroid Hydroxylases / Q000737:chemistry
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C065407:CYP2C5 protein, Oryctolagus cuniculus; C450259:CYP2C8 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase; D010089:Oxidoreductases, N-Demethylating