Species differences in coumarin metabolism : a molecular modelling evaluation of CYP2A interactions
article
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 (CYP2AS) 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.
2. The metabolism of coumarin via 7-hydroxylation in the human (CYP2A6) and mouse (CYP2AS) 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.
Topics
CoumarinCytochrome P450Cytochrome P450 2A1Cytochrome P450 2A5Cytochrome P450 2A6Unclassified drugEpoxidationHydrogen bondHydroxylationLipophilicityMammalMetabolismMolecular modelQuantitative structure activity relationAmino Acid SequenceAnimalsAryl Hydrocarbon HydroxylasesCatalytic DomainCoumarinsCytochrome P-450 Enzyme SystemHumansHydrogen BondingMiceMixed Function OxygenasesModels, MolecularMolecular Sequence DataMutagenesis, Site-DirectedQuantitative Structure-Activity RelationshipRatsSequence Homology, Amino AcidSpecies SpecificitySteroid HydroxylasesSubstrate SpecificityThermodynamicsMammalia
TNO Identifier
42380
Source
Xenobiotica, 32(7), pp. 547-561.
Pages
547-561
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