Mechanism of Action of Compound-13: an α1-Selective Small Molecule Activator of AMPK

Roger W. Hunter, Marc Foretz, Laurent Bultot, Morgan D. Fullerton, Maria Deak, Fiona A. Ross, Simon A. Hawley, Natalia Shpiro, Benoit Viollet, Denis Barron, Bruce E. Kemp, Gregory R. Steinberg, D. Grahame Hardie, Kei Sakamoto (Lead / Corresponding author)

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    72 Citations (Scopus)
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    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 a1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of a2-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 a2, containing the equivalent region from a1 thought to interact with AMP bound in site 3 of the ? 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 a1 than of a2, ß1, or ß2.
    Original languageEnglish
    Pages (from-to)866-879
    Number of pages14
    JournalChemistry & Biology
    Volume21
    Issue number7
    Early online date17 Jul 2014
    DOIs
    Publication statusPublished - 17 Jul 2014

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