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The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

2012; American Association for the Advancement of Science; Volume: 336; Issue: 6083 Linguagem: Inglês

10.1126/science.1215327

1095-9203

Simon A. Hawley, Morgan D. Fullerton, Fiona A. Ross, Jonathan D. Schertzer, Cyrille Chevtzoff, Katherine J. Walker, Mark Peggie, Darya Zibrova, Kevin A. Green, Kirsty J. Mustard, Bruce E. Kemp, Kei Sakamoto, Gregory R. Steinberg, D. Grahame Hardie,

Autophagy in Disease and Therapy

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 More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo.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.