Species differences in coumarin metabolism: a molecular modelling evaluation of CYP2A interactions
- 1 January 2002
- journal article
- research article
- Published by Taylor & Francis in Xenobiotica
- Vol. 32 (7) , 547-561
- https://doi.org/10.1080/00498250210128693
Abstract
1. An account of the differences in coumarin metabolism between several mammalian species, including man, is reported. 2. The metabolism of coumarin via 7-hydroxylation in the human (CYP2A6) and mouse (CYP2A5) enzymes is explained in terms of molecular modelling of the active site interactions, whereas the rat orthologue (CYP2A1) exhibits 3,4-epoxidation of coumarin, which is also consistent with the modelled interaction between enzyme and substrate. 3. In addition, quantitative structure-activity relationships (QSARs) for coumarin 7-hydroxylation in wild-type and mutant CYP2A5 show the importance of amino acid residue properties for substrate binding, whereas QSARs for CYP2A6 substrates indicate the importance of hydrogen bonding and lipophilicity for favourable interactions with the enzyme.Keywords
This publication has 11 references indexed in Scilit:
- High-resolution crystal structure of cytochrome P450camPublished by Elsevier ,2005
- Homology modelling of human CYP2 family enzymes based on the CYP2C5 crystal structureXenobiotica, 2002
- CYP2A6: a human coumarin 7-hydroxylaseToxicology, 2000
- Mammalian Microsomal Cytochrome P450 MonooxygenaseMolecular Cell, 2000
- The structure of the cytochrome p450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acidNature Structural & Molecular Biology, 1997
- Structural flexibility and functional versatility of cytochrome P450 and rapid evolutionMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1996
- Crystal Structure of Hemoprotein Domain of P450BM-3, a Prototype for Microsomal P450'sScience, 1993
- Site-directed mutagenesis of cytochrome P450s CYP2A1 and CYP2A2: influence of the distal helix on the kinetics of testosterone hydroxylationBiochemistry, 1992
- Automatic log P estimation based on combined additive modeling methodsJournal of Computer-Aided Molecular Design, 1990
- Crystal structure of substrate-free Pseudomonas putida cytochrome P-450Biochemistry, 1986