Title: Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release
Authors: Scott, JW
Galic, S
Graham, KL
Foitzik, R
Ling, NXY
Dite, TA
Issa, SMA
Langendorf, CG
Weng, QP
Thomas, HE
Kay, TW
Birnberg, NC
Steinberg, GR
Kemp, BE
Oakhill, JS
Issue Year: 2015
Publisher CELL PRESS
Series Chem. Biol.:
Abstract The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing alpha beta gamma 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 beta 1 or beta 2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the beta 2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of beta 2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by beta/beta 2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a beta 2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.
URI: https://publications.svi.edu.au/publications/2259
Other Identifiers 10.1016/j.chembiol.2015.05.011
Publication type Article
Grant ID GNT1049197