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Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK.

Research paper by Roger W RW Hunter, Marc M Foretz, Laurent L Bultot, Morgan D MD Fullerton, Maria M Deak, Fiona A FA Ross, Simon A SA Hawley, Natalia N Shpiro, Benoit B Viollet, Denis D Barron, Bruce E BE Kemp, Gregory R GR Steinberg, D Grahame DG Hardie, Kei K Sakamoto

Indexed on: 19 Jul '14Published on: 19 Jul '14Published in: Chemistry & Biology



Abstract

AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.

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