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Functional analysis of CYP2D6.31 variant: Homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution by Delphine Allorge; Didier Bréant; Jacky Harlow; Joey Chowdry; Jean‐Marc Lo‐Guidice; Dany Chevalier; Christelle Cauffiez; Michel Lhermitte; Frank E. Blaney; Geoffrey T. Tucker; Franck Broly; S. Wynne Ellis is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## Abstract Cytochrome P450 2D6 (CYP2D6) is an important human drug‐metabolizing enzyme that exhibits a marked genetic polymorphism. Numerous __CYP2D6__ alleles have been characterized at a functional level, although the consequences for expression and/or catalytic activity of a substantial number of rare variants remain to be investigated. One such allele, __CYP2D6__\*__31__, is characterized by mutations encoding three amino acid substitutions: Arg296Cys, Arg440His and Ser486Thr. The identification of this allele in an individual with an apparent __in vivo__ poor metabolizer phenotype prompted us to analyze the functional consequence of these substitutions on enzyme activity using yeast as a heterologous expression system. We demonstrated that the Arg440His substitution, alone or in combination with Arg296Cys and/or Ser486Thr, altered the respective kinetic parameters [__K__~__m__~ (μ__M__) and __k__~cat~ (min^−1^)] of debrisoquine 4‐hydroxylation (wild‐type, 25; 0.92; variants, 43–68; 0.05–0.11) and dextromethorphan __O__‐demethylation (wild‐type, 1; 4.72; variants, 12–23; 0.64‐1.43), such that their specificity constants (__k__~cat~/__K__~__m__~) were decreased by more than 95%

Who reads Functional analysis of CYP2D6.31 variant: Homology modeling suggests possible disruption of redox partner interaction by Arg440His substitution?

Author

Delphine Allorge; Didier Bréant; Jacky Harlow; Joey Chowdry; Jean‐Marc Lo‐Guidice; Dany Chevalier; Christelle Cauffiez; Michel Lhermitte; Frank E. Blaney; Geoffrey T. Tucker; Franck Broly; S. Wynne Ellis

Publisher

John Wiley and Sons; Wiley (John Wiley & Sons); Wiley-Liss Inc; Wiley (ISSN 0887-3585)

Published

2005

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)