The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

被引：589

作者：

Hawley, Simon A. ^{[1
]}

Fullerton, Morgan D. ^{[2
,3
,4
]}

Ross, Fiona A. ^{[1
]}

Schertzer, Jonathan D. ^{[2
,3
,4
]}

Chevtzoff, Cyrille ^{[1
]}

Walker, Katherine J. ^{[1
]}

Peggie, Mark W. ^{[5
]}

Zibrova, Darya ^{[5
]}

Green, Kevin A. ^{[1
]}

Mustard, Kirsty J. ^{[1
]}

Kemp, Bruce E. ^{[6
,7
]}

Sakamoto, Kei ^{[5
]}

Steinberg, Gregory R. ^{[2
,3
,4
,6
,7
]}

Hardie, D. Grahame ^{[1
]}

机构：

[1] Univ Dundee, Coll Life Sci, Div Cell Signalling & Immunol, Dundee DD1 5EH, Scotland

[2] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada

[3] McMaster Univ, Dept Med, Div Endocrinol, Hamilton, ON L8N 3Z5, Canada

[4] McMaster Univ, Dept Med, Div Metab, Hamilton, ON L8N 3Z5, Canada

[5] Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland

[6] St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia

[7] Univ Melbourne, Dept Med, Fitzroy, Vic 3065, Australia

来源：

SCIENCE | 2012年 / 336卷 / 6083期

基金：

加拿大健康研究院; 英国医学研究理事会; 澳大利亚研究理事会; 英国惠康基金;

关键词：

MECHANISM; ASPIRIN; PHOSPHORYLATION; INHIBITION; METABOLISM; SALSALATE; A-769662; CELLS; BETA;

D O I：

10.1126/science.1215327

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.

引用

页码：918 / 922

页数：5

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