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Mechanism of action of compound-13: an ?1-selective small molecule activator of AMPK.

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 ?1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of ?2-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 ?2, containing the equivalent region from ?1 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 ?1 than of ?2, ?1, or ?2.

SUBMITTER: Hunter RW

PROVIDER: S-EPMC4104029 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

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

Chemistry & biology 20140701 7

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 ef ...[more]

PMID: 25036776

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Mechanism of action of compound-13: an ?1-selective small molecule activator of AMPK.

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

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