Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity

	Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity
	Xu, X; Zhao, JY; Xu, Z; Peng, BZ; Huang, QH; Arnold, E; Ding, JP
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2004
卷号	279 期号:32 页码:33946-33957
通讯作者	Ding, JP (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Key Lab Prote, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,jpding@sibs.ac.cn
英文摘要	Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their regulatory mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved alpha-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH; a partially unraveled alpha-helix in the semi-open, intermediate form; and an alpha-helix in the closed, active form. The side chain of Asp(279) of this segment occupies the isocitrate-binding site and forms hydrogen bonds with Ser(94) ( the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-regulatory mechanism for HcIDH that mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	PEROXISOMAL BETA-OXIDATION ; CRYSTAL-STRUCTURE ; CELLULAR DEFENSE ; FATTY-ACIDS ; PHOSPHORYLATION ; ENZYME ; DAMAGE ; SITE ; KINASE/PHOSPHATASE ; INACTIVATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000223039700105
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2184]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Xu, X,Zhao, JY,Xu, Z,et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2004,279(32):33946-33957.
APA	Xu, X.,Zhao, JY.,Xu, Z.,Peng, BZ.,Huang, QH.,...&Ding, JP.(2004).Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity.JOURNAL OF BIOLOGICAL CHEMISTRY,279(32),33946-33957.
MLA	Xu, X,et al."Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity".JOURNAL OF BIOLOGICAL CHEMISTRY 279.32(2004):33946-33957.