Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8

	Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8
	Jiang, HL; Zhong, FF; Sun, L; Feng, WY; Huang, ZX; Tan, XS; Feng WY(丰伟悦)
刊名	AMINO ACIDS
	2011
卷号	40 期号:4 页码:1195-1204
关键词	Structure-function relationship Polymorphism CYP2C8 Drug metabolism Individualized medication
通讯作者	[Jiang, Hualin ; Zhong, Fangfang ; Sun, Lu ; Huang, Zhong-Xian ; Tan, Xiangshi] Fudan Univ, Dept Chem, Shanghai 200433, Peoples R China ; [Jiang, Hualin ; Zhong, Fangfang ; Sun, Lu ; Huang, Zhong-Xian ; Tan, Xiangshi] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China ; [Feng, Weiyue] Chinese Acad Sci, Inst High Energy Phys, Beijing 100049, Peoples R China
英文摘要	The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
研究领域[WOS]	Biochemistry & Molecular Biology
原文出处	SCI
语种	英语
WOS记录号	WOS:000288546700016
内容类型	期刊论文
源URL	[http://ir.ihep.ac.cn/handle/311005/239165]
专题	高能物理研究所_多学科研究中心高能物理研究所_粒子天体物理中心
作者单位	中国科学院高能物理研究所
推荐引用方式 GB/T 7714	Jiang, HL,Zhong, FF,Sun, L,et al. Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8[J]. AMINO ACIDS,2011,40(4):1195-1204.
APA	Jiang, HL.,Zhong, FF.,Sun, L.,Feng, WY.,Huang, ZX.,...&丰伟悦.(2011).Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8.AMINO ACIDS,40(4),1195-1204.
MLA	Jiang, HL,et al."Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8".AMINO ACIDS 40.4(2011):1195-1204.