Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells

doi:10.1074/jbc.M710114200

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	Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells
	Pang, Tao 1; Zhang, Zhen-Shan 2; Gu, Min1 ; Qiu, Bei-Ying 1; Yu, Li-Fang 1; Cao, Peng-Rong 1; Shao, Wei 1; Su, Ming-Bo 1; Li, Jing-Ya1 ; Nan, Fa-Jun1
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2008-06-06
卷号	283 期号:23 页码:16051-16060
ISSN号	0021-9258
DOI	10.1074/jbc.M710114200
文献子类	Article
英文摘要	AMP-activated protein kinase (AMPK) serves as an energy sensor and is considered a promising drug target for treatment of type II diabetes and obesity. A previous report has shown that mammalian AMPK alpha 1 catalytic subunit including autoinhibitory domain was inactive. To test the hypothesis that small molecules can activate AMPK through antagonizing the autoinhibition in alpha subunits, we screened a chemical library with inactive human alpha 1(394) (alpha 1, residues 1-394) and found a novel small-molecule activator, PT1, which dose-dependently activated AMPK alpha 1(394), alpha 1(335), alpha 2(398), and even heterotrimer alpha 1 beta 1 gamma 1. Based on PT1-docked AMPK alpha 1 subunit structure model and different mutations, we found PT1 might interact with Glu-96 and Lys-156 residues near the autoinhibitory domain and directly relieve autoinhibition. Further studies using L6 myotubes showed that the phosphorylation of AMPK and its downstream substrate, acetyl-CoA carboxylase, were dose-dependently and time-dependently increased by PT1 without an increase in cellular AMP: ATP ratio. Moreover, in HeLa cells deficient in LKB1, PT1 enhanced AMPK phosphorylation, which can be inhibited by the calcium/calmodulin-dependent protein kinase kinases inhibitor STO-609 and AMPK inhibitor compound C. PT1 also lowered hepatic lipid content in a dose-dependent manner through AMPK activation in HepG2 cells, and this effect was diminished by compound C. Taken together, these data indicate that this small-molecule activator may directly activate AMPK via antagonizing the autoinhibition in vitro and in cells. This compound highlights the effort to discover novel AMPK activators and can be a useful tool for elucidating the mechanism responsible for conformational change and autoinhibitory regulation of AMPK.
WOS关键词	FATTY-ACID OXIDATION ; GAMMA-SUBUNIT ISOFORMS ; METABOLIC SYNDROME ; CATALYTIC SUBUNIT ; UPSTREAM KINASE ; GLUCOSE-UPTAKE ; RAT-LIVER ; METFORMIN ; MECHANISM ; CASCADE
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000256332500063
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272894]
专题	国家新药筛选中心
通讯作者	Nan, Fa-Jun
作者单位	1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China; 2.Roche R&D Ctr China Ltd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Pang, Tao,Zhang, Zhen-Shan,Gu, Min,et al. Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(23):16051-16060.
APA	Pang, Tao.,Zhang, Zhen-Shan.,Gu, Min.,Qiu, Bei-Ying.,Yu, Li-Fang.,...&Li, Jia.(2008).Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells.JOURNAL OF BIOLOGICAL CHEMISTRY,283(23),16051-16060.
MLA	Pang, Tao,et al."Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells".JOURNAL OF BIOLOGICAL CHEMISTRY 283.23(2008):16051-16060.