title: The ancient drug salicylate directly activates AMP-activated protein kinase.
abstract: 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 More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo.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.
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hawley
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Ross
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: Cyrille
authors.initials: C
authors.lastname: Chevtzoff
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Walker
authors.forename: Mark W
authors.initials: MW
authors.lastname: Peggie
authors.forename: Darya
authors.initials: D
authors.lastname: Zibrova
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Green
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: Mustard
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001665:Binding Sites; D001713:Biphenyl Compounds; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D012459:Salicylates / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D020536:Enzyme Activators; D011753:Pyrones; D012459:Salicylates; D013876:Thiophenes; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; D001241:Aspirin