title: ATP sensitive bi-quinoline activator of the AMP-activated protein kinase.
abstract: The AMP-activated protein kinase (AMPK) regulates cellular and whole-body energy balance in response to changes in adenylate charge and hormonal signals. Activation of AMPK in tissues such as skeletal muscle and liver reverses many of the metabolic defects associated with obesity and Type 2 diabetes. Here we report a bi-quinoline (JJO-1) that allosterically activates all AMPK αβγ isoforms in vitro except complexes containing the γ3 subunit. JJO-1 does not directly activate the autoinhibited α subunit kinase domain and differs among other known direct activators of AMPK in that allosteric activation occurs only at low ATP concentrations, and is not influenced by either mutation of the γ subunit adenylate-nucleotide binding sites or deletion of the β subunit carbohydrate-binding module. Our findings indicate that AMPK has multiple modes of allosteric activation that may be exploited to design isoform-specific activators as potential therapeutics for metabolic diseases.
authors: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia. Electronic address: jscott@svi.edu.au.
authors: John W
authors: JW
authors: Scott
authors: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia.
authors: Jonathan S
authors: JS
authors: Oakhill
authors: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia.
authors: Naomi X Y
authors: NX
authors: Ling
authors: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia.
authors: Christopher G
authors: CG
authors: Langendorf
authors: Cancer Therapeutics CRC Pty. Ltd., Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
authors: Richard C
authors: RC
authors: Foitzik
authors: St. Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia.
authors: Bruce E
authors: BE
authors: Kemp
authors: Biomedical Research Group, BMB, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
authors: Olaf-Georg
authors: OG
authors: Issinger
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D011804:Quinolines; D000255:Adenosine Triphosphate; C037219:quinoline; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Activator; Allosteric; Drug; Isoform-specific; Phosphorylation