Active-site topologies of human CYP2D6 and its aspartate-301 → glutamate, asparagine, and glycine mutants

Richard Mackman, Richard A. Tschirret-Guth, Gillian Smith, Graham P. Hayhurst, S. Wynne Ellis, Martin S. Lennard, Geoffrey T. Tucker, C. Roland Wolf, Paul R. Ortiz de Montellano

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    44 Citations (Scopus)

    Abstract

    Cytochrome P450 2D6 (CYP2D6) catalyzes the oxidation of substrates with a positively charged nitrogen atom 5-7 angstroms from the site of the oxidation. The active-site topology of CYP2D6 is examined here with phenyl-, 2-naphthyl-, and p-biphenyldiazene, which react with P450 enzymes to form sigma-bonded aryl-iron (Fe-Ar) complexes. Ferricyanide-mediated migration of the aryl group from the iron to the porphyrin nitrogens produces the N-arylprotoporphyrin IX regioisomers (NB:NA:NC:ND, in which the aryl group is bound to the nitrogen of pyrrole rings B, A, C, and D, respectively) in the following ratios (zero means
    Original languageEnglish
    Pages (from-to)134-140
    Number of pages7
    JournalArchives of Biochemistry and Biophysics
    Volume331
    Issue number1
    DOIs
    Publication statusPublished - 1996

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