title: Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release.
abstract: The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia. Electronic address: jscott@svi.edu.au.
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.affiliation: Immunology and Diabetes Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.affiliation: Cancer Therapeutics CRC Pty Ltd, Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Foitzik
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Naomi X Y
authors.initials: NX
authors.lastname: Ling
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Toby A
authors.initials: TA
authors.lastname: Dite
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Samah M A
authors.initials: SM
authors.lastname: Issa
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Langendorf
authors.affiliation: Mercury Therapeutics Inc., 175 East New Boston Street, Woburn, MA 01801, USA.
authors.forename: Qing Ping
authors.initials: QP
authors.lastname: Weng
authors.affiliation: Immunology and Diabetes Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: Immunology and Diabetes Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.affiliation: Mercury Therapeutics Inc., 175 East New Boston Street, Woburn, MA 01801, USA.
authors.forename: Neal C
authors.initials: NC
authors.lastname: Birnberg
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC 3065, Australia. Electronic address: joakhill@svi.edu.au.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Oakhill
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006912:Hydroxyquinolines; D007328:Insulin; C000606251:MT47-100; D020033:Protein Isoforms; D055372:AMP-Activated Protein Kinases; D005947:Glucose