Changes in the Enzymatic Properties of CYP2D6 by the Substitution of Phenylalanine at Position 120 by Alanine
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概要
- 論文の詳細を見る
The functional roles of phenylalanine at position 120(Phe-120) in the oxidation of bunitrolol (BTL), debrisoquine (DB) and bufuralol (BF) by cytochrome P450 2D6 (CYP2D6) were examined using a yeast cell expression system (Saccharomyces cerevisiae AH-22 strain). The substitution of Phe-120 by alanine markedly increased the activities of enantiomeric BTL 4-hydroxylase and DB 4-hydroxylase, whereas it did not remarkably affect BF 1"-hydroxylase activities. Kinetic studies revealed that the substitution of Phe-120 by alanine increased the Km and Vmax values for enantiomeric BTL 4-hydroxylation, but increased only the Vmax value for DB 4-hydroxylation without changing the Km value. Km and Vmax values for BF 1"-hydroxylation were similar between the mutant and the wild-type. The dissociation constants of the mutant calculated from the binding spectra for BTL enantiomers were higher than those of the wild-type, suggesting that the substitution of Phe-120 by alanine decreased the affinity of CYP2D6 for BTL enantiomers. These results indicate that Phe-120 has an important role in the oxidation of substrates by CYP2D6.
- 社団法人日本薬学会の論文
- 2004-10-01
著者
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NARIMATSU Shizuo
Laboratories of Health Chemistry,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
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Hichiya Hiroyuki
Laboratories Of Health Chemistry Okayama University
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Hichiya Hiroyuki
岡山大学 薬学部薬品構造物性化学
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Hashimoto Hiroki
Laboratories Of Pharmaceutical Physical Chemistry Okayama University
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Yamamoto S
Fukuoka Univ. Fukuoka Jpn
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ISOBE Takashi
Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University
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HANIOKA Nobumitsu
Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University
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YAMAMOTO Shigeo
Laboratory of Biomolecular Sciences, Faculty of Pharmaceutical Sciences, Okayama University
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Masuda Kazufumi
Laboratories of Pharmaceutical Physical Chemistry, Okayama University
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Tamagake Keietsu
Laboratories of Pharmaceutical Physical Chemistry, Okayama University
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Okuda Yukie
Laboratories of Health Chemistry, Okayama University
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Tsuzuki Daisuke
Laboratories of Health Chemistry, Okayama University
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Narimatsu Shizuo
Laboratories Of Health Chemistry Okayama University
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Narimatsu Shizuo
Laboratories Health Chemistry Faculty Of Pharmaceutical Sciences Okayama University
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Hanioka Nobumitsu
Laboratories Of Health Chemistry Okayama University
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Okuda Yukie
Laboratories Of Health Chemistry Okayama University
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Isobe Takashi
Laboratories Of Health Chemistry Okayama University
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Masuda Kazufumi
School Of Pharmacy Shujitsu University
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Yamamoto Shigeo
Laboratories Of Biomolecular Sciences Faculty Of Pharmaceutical Sciences Okayama University
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Yamamoto S
Department Of Pharmacology And Pharmaceutics Graduate School Of Natural Science And Technology Kanaz
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Tsuzuki Daisuke
Laboratories Of Health Chemistry Okayama University
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Tamagake Keietsu
Laboratories Of Pharmaceutical Physical Chemistry Okayama University
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