Insights into the inhibitory mechanisms of NADH on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase

doi:10.1038/s41598-018-21584-7

	Insights into the inhibitory mechanisms of NADH on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase
	Liu, Yabing 1; Hu, Lejia 1; Ma, Tengfei 2; Yang, Jun 2; Ding, Jianping2,3
	2018-02-16
发表期刊	SCIENTIFIC REPORTS
ISSN	2045-2322
卷号	8
发表状态	已发表
DOI	10.1038/s41598-018-21584-7
摘要	Human NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the oxidative decarboxylation of isocitrate in the citric acid cycle. In the alpha(2)beta gamma heterotetramer of NAD-IDH, the gamma subunit plays the regulatory role and the beta subunit the structural role. Previous biochemical data have shown that mammalian NAD-IDHs can be inhibited by NADH; however, the molecular mechanism is unclear. In this work, we show that the alpha beta, alpha gamma and alpha(2)beta gamma enzymes of human NAD-IDH can be inhibited by NADH, and further determine the crystal structure of the alpha gamma heterodimer bound with an Mg2+ and an NADH at the active site and an NADH at the allosteric site, which resembles that of the inactive alpha(Mg)gamma heterodimer. The NADH at the active site occupies the binding site for NAD(+) and prevents the binding of the cofactor. The NADH at the allosteric site occupies the binding sites for ADP and citrate and blocks the binding of the activators. The biochemical data confirm that the NADH binding competes with the binding of NAD(+) and the binding of citrate and ADP, and the two effects together contribute to the NADH inhibition on the activity. These findings provide insights into the inhibitory mechanisms of the alpha gamma heterodimer by NADH.
收录类别	SCI ; SCIE
语种	英语
资助项目	Chinese Academy of Sciences[XDB08010302]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000425284900014
出版者	NATURE PUBLISHING GROUP
WOS关键词	AMINO-ACID-SEQUENCES ; PIG-HEART ; MOLECULAR-CLONING ; BETA-SUBUNITS ; BOVINE HEART ; CITRATE ; ADP
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/18286
专题	生命科学与技术学院_特聘教授组_丁建平组
通讯作者	Ding, Jianping
作者单位	1.Shanghai Univ, Sch Life Sci, 333 Nanchen Rd, Shanghai 200444, Peoples R China 2.Chinese Acad Sci, Natl Ctr Prot Sci Shanghai, Inst Biochem & Cell Biol,Shanghai Sci Res Ctr, Shanghai Inst Biol Sci,State Key Lab Mol Biol,CAS, 320Yue Yang Rd, Shanghai 200031, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Liu, Yabing,Hu, Lejia,Ma, Tengfei,et al. Insights into the inhibitory mechanisms of NADH on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase[J]. SCIENTIFIC REPORTS,2018,8.
APA	Liu, Yabing,Hu, Lejia,Ma, Tengfei,Yang, Jun,&Ding, Jianping.(2018).Insights into the inhibitory mechanisms of NADH on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase.SCIENTIFIC REPORTS,8.
MLA	Liu, Yabing,et al."Insights into the inhibitory mechanisms of NADH on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase".SCIENTIFIC REPORTS 8(2018).