Active-Site Topologies of Human CYP2D6 and Its Aspartate-301 → Glutamate, Asparagine, and Glycine Mutants

Active-Site Topologies of Human CYP2D6 and Its Aspartate-301 → Glutamate, Asparagine, and Glycine Mutants

Cytochrome P450 2D6 (CYP2D6) catalyzes the oxidation of substrates with a positively charged nitrogen atom 5–7 Å from the site of the oxidation. The active-site topology of CYP2D6 is examined here with phenyl-, 2-naphthyl-, andp-biphenyldiazene, which react with P450 enzymes to form σ-bonded aryl–ir...

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Veröffentlicht in:Archives of biochemistry and biophysics 1996-07, Vol.331 (1), p.134-140
Hauptverfasser: Mackman, Richard, Tschirret-Guth, Richard A., Smith, Gillian, Hayhurst, Graham P., Ellis, S.Wynne, Lennard, Martin S., Tucker, Geoffrey T., Wolf, C.Roland, Ortiz de Montellano, Paul R.
Format: Artikel
Sprache:eng
Schlagworte:
Asparagine
Aspartic Acid
Binding Sites
Cytochrome P-450 CYP2D6
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - genetics
Electrochemistry
Glutamic Acid
Glycine
Humans
Hydrazines - chemistry
Imines - chemistry
Mixed Function Oxygenases - chemistry
Mixed Function Oxygenases - genetics
Models, Molecular
Molecular Structure
Mutation
Protoporphyrins - chemistry
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Structure-Activity Relationship
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Zusammenfassung:Cytochrome P450 2D6 (CYP2D6) catalyzes the oxidation of substrates with a positively charged nitrogen atom 5–7 Å from the site of the oxidation. The active-site topology of CYP2D6 is examined here with phenyl-, 2-naphthyl-, andp-biphenyldiazene, which react with P450 enzymes to form σ-bonded aryl–iron (Fe–Ar) complexes. Ferricyanide-mediated migration of the aryl group from the iron to the porphyrin nitrogens produces theN-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
ISSN:0003-9861
1096-0384
DOI:10.1006/abbi.1996.0291