title: Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes.
abstract: The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the beta subunit carbohydrate-binding module and residues from the gamma subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the beta1 subunit. Our findings highlight the regulatory role played by the beta subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.
authors.affiliation: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, VIC Australia. jscott@svi.edu.au
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.forename: Bryce J W
authors.initials: BJ
authors.lastname: van Denderen
authors.forename: Sebastian B
authors.initials: SB
authors.lastname: Jorgensen
authors.forename: Jane E
authors.initials: JE
authors.lastname: Honeyman
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Oakhill
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Iseli
authors.forename: Ann
authors.initials: A
authors.lastname: Koay
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gooley
authors.forename: David
authors.initials: D
authors.lastname: Stapleton
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds; D019556:COS Cells; D050260:Carbohydrate Metabolism; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D011753:Pyrones / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D013379:Substrate Specificity; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D007527:Isoenzymes; D011753:Pyrones; D011994:Recombinant Proteins; D013876:Thiophenes; D000249:Adenosine Monophosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile