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

TY - JOUR

T1 - Active-site topologies of human CYP2D6 and its aspartate-301 → glutamate, asparagine, and glycine mutants

AU - Mackman, Richard

AU - Tschirret-Guth, Richard A.

AU - Smith, Gillian

AU - Hayhurst, Graham P.

AU - Ellis, S. Wynne

AU - Lennard, Martin S.

AU - Tucker, Geoffrey T.

AU - Wolf, C. Roland

AU - Ortiz de Montellano, Paul R.

N1 - This work was supported by National Institutes of Health Grant GM25515 (P.R.O.M.) and the Wellcome Trust Grant 038735 (M.S.L., G.T.T., C.R.W.). Support for the Liver Center core facilities at the University of California, San Francisco, was provided by Grant 5 P30 DK26743

PY - 1996

Y1 - 1996

N2 - 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

AB - 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

U2 - 10.1006/abbi.1996.0291

DO - 10.1006/abbi.1996.0291

M3 - Article

C2 - 8660692

SN - 0003-9861

VL - 331

SP - 134

EP - 140

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

IS - 1

ER -