Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family
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AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases, such as type 2 diabetes, and consequently AMPK is a target for treatment of these diseases. Recently, a small molecule activator (A-769662) of AMPK was identified that had beneficial effects on metabolism in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the gamma subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the beta subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, while only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly, this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK, which in turn may help in the identification of other AMPK activators.
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Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK.
“Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK [26,28,38,39].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [38]
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- Authors
- Sanders, M. J., Ali, Z. S., Hegarty, B. D., Heath, R., Snowden, M. A., & Carling, D.
- Affiliations
- Hammersmith Hospital (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Carling, David
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 282
- Issue
- 45
- Pages
- 32539-32548
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2085558309
- Cited by
- 347
- References
- 47
- Citations by year
- 2026: 12 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 13 · 2021: 20 · 2020: 18 · 2019: 14 · 2018: 31 · 2017: 21 · 2016: 28 · 2015: 19 · 2014: 40 · 2013: 23 · 2012: 16
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AMPK, A769662, allosteric activation, energy homeostasis, type 2 diabetes, ob/ob mice
- MeSH terms
- Biphenyl Compounds, Cell Line, Enzyme Activation, Humans, Multienzyme Complexes, Mutation, Phosphorylation, Protein Binding, Pyridines, Pyrones, Thiophenes, Threonine, Protein Serine-Threonine Kinases, Protein Subunits, AMP-Activated Protein Kinases
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