Molecular modelling of human CYP1B1 substrate interactions and investigation of allelic variant effects on metabolism.
Molecular modelling of human CYP1B1 based on homology with the mammalian P450, CYP2C5, of known three-dimensional structure is reported. The enzyme model has been used to investigate the likely mode of binding for selected CYP1B1 substrates, particularly with regard to the possible effects of allelic variants of CYP1B1 on metabolism. In general, it appears that the CYP1B1 model is consistent with known substrate selectivity for the enzyme, and the sites of metabolism can be rationalized in terms of specific contacts with key amino acid residues within the CYP1B1 heme locus. Furthermore, a mode of binding interaction for the inhibitor, alpha-naphthoflavone, is presented which accords with currently available information. The current paper shows that a combination of molecular modelling and experimental determinations on the substrate metabolism for CYP1B1 allelic variants can aid in the understanding of structure-function relationships within P450 enzymes.
School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. d.lewis@surrey.ac.uk
David F V
DF
Lewis
Elizabeth M J
EM
Gillam
Steven A
SA
Everett
Tsutomu
T
Shimada
D000483:Alleles; D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D014644:Genetic Variation; D006801:Humans; D021621:Imaging, Three-Dimensional; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1