Journal of Health Science
Online ISSN : 1347-5207
Print ISSN : 1344-9702
ISSN-L : 1344-9702
Changes in the Enzymatic Properties of CYP2D6 by the Substitution of Phenylalanine at Position 120 by Alanine
Kazufumi MasudaHiroki HashimotoKeietsu TamagakeYukie OkudaDaisuke TsuzukiTakashi IsobeHiroyuki HichiyaNobumitsu HaniokaShigeo YamamotoShizuo Narimatsu
ジャーナル フリー

2004 年 50 巻 5 号 p. 503-510


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.

© 2004 by The Pharmaceutical Society of Japan
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