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Titolo:
Functional evaluation of cytochrome P450 2D6 with Gly(42)Arg substitution expressed in Saccharomyces cerevisiae
Autore:
Tsuzuki, D; Takemi, C; Yamamoto, S; Tamagake, K; Imaoka, S; Funae, Y; Kataoka, H; Shinoda, S; Narimatsu, S;
Indirizzi:
Okayama Univ, Fac Pharmaceut Sci, Lab Hlth Chem, Okayama 7008530, Japan Okayama Univ Okayama Japan 7008530 Lab Hlth Chem, Okayama 7008530, Japan Okayama Univ, Fac Pharmaceut Sci, Lab Biomol Sci, Okayama 7008530, Japan Okayama Univ Okayama Japan 7008530 ab Biomol Sci, Okayama 7008530, Japan Okayama Univ, Fac Pharmaceut Sci, Phys Chem Lab, Okayama 7008530, Japan Okayama Univ Okayama Japan 7008530 Phys Chem Lab, Okayama 7008530, Japan Okayama Univ, Fac Pharmaceut Sci, Environm Chem Lab, Okayama 7008530, Japan Okayama Univ Okayama Japan 7008530 ronm Chem Lab, Okayama 7008530, Japan Osaka City Univ, Sch Med, Chem Lab, Osaka 545, Japan Osaka City Univ Osaka Japan 545 niv, Sch Med, Chem Lab, Osaka 545, Japan
Titolo Testata:
PHARMACOGENETICS
fascicolo: 8, volume: 11, anno: 2001,
pagine: 709 - 718
SICI:
0960-314X(200111)11:8<709:FEOCP2>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
POOR METABOLIZER PHENOTYPE; BUNITROLOL 4-HYDROXYLATION; CRYSTAL-STRUCTURE; MEMBRANE-BINDING; LIVER-MICROSOMES; CYP2D6; VARIANT; DEBRISOQUINE; MUTATIONS; SPARTEINE;
Keywords:
CYP2D6 variant; Saccharomyces cerevisiae; gene expression; debrisoquine; bunitrolol;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Narimatsu, S Okayama Univ, Fac Pharmaceut Sci, Lab Hlth Chem, 1-1-1 Tsushima Naka, Okayama 7008530, Japan Okayama Univ 1-1-1 Tsushima Naka Okayama Japan 7008530 Japan
Citazione:
D. Tsuzuki et al., "Functional evaluation of cytochrome P450 2D6 with Gly(42)Arg substitution expressed in Saccharomyces cerevisiae", PHARMACOGEN, 11(8), 2001, pp. 709-718

Abstract

A single amino acid-substituted mutant protein, CYP2D6 (G42R) was expressed in Saccharomyces cerevisiae and its enzymatic properties were compared with those of other single (P34S, R296C and S486T) and double amino acid-substituted mutant proteins (P34S/S486T and R296C/S486T) expressed in yeast cells, all of which were known to occur in the CYP2D6 gene as single nucleotide polymorphisms. The protein levels of G42R, P34S and P34S/S486T in microsomal fractions and their oxidation capacities towards debrisoquine as a prototypic substrate and bunitrolol as a chiral substrate were different from those of wild-type CYP2D6, while the R296C, S486T and R296C/S486T behaved similarly to the wild-type in these indices. The CYP contents both in yeast microsomal and in whole cell fractions indicated that some part of G42R protein was localized in the endoplasmic reticulum membrane fraction, whereas most of G42R protein was in some subcellular fractions other than endoplasmic reticulum. In kinetic analysis, the G42R substitution increased apparent K-m and decreased V-max for debrisoquine 4-hydroxylation, while it increased both K-m and V-max for bunitrolol 4-hydroxylation. The P34S substitution did not drastically change K-m. but decreased V-max for debrisoquine 4-hydroxylation, whereas K-m was increased and V-max unchanged or decreased for bunitrolol 4-hydroxylation by P34S substitution. These results suggest that the G42R substitution causes a change in the CYP2D6 conformation, which maybe different from the change produced by the P34S substitution. Pharmacogenetics 11:709-718 (C) 2001 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 16:12:54