Mechanism of Action of Compound-13: An α1-Selective Small Molecule Activator of AMPK Academic Article uri icon

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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 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.

authors

  • Hunter, Roger W
  • Foretz, Marc
  • Bultot, Laurent
  • Fullerton, Morgan D
  • Deak, Maria
  • Ross, Fiona A
  • Hawley, Simon A
  • Shpiro, Natalia
  • Viollet, Benoit
  • Barron, Denis
  • Kemp, Bruce E
  • Steinberg, Gregory
  • Hardie, D Grahame
  • Sakamoto, Kei

publication date

  • July 2014

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