The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Defining the Mechanism of Activation of AMP-activated Protein Kinase by the Small Molecule A-769662, a Member of the Thienopyridone Family
Open accessAbstract
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 [26,28,38,39].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [38]
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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) · Nature Medicine · doi:10.1038/nm788 · Cited by 4,238
Self-citationKahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799
Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
Minokoshi, Y., Kim, Y.-B., Peroni, O. D., Fryer, L. G. D., Müller, C., Carling, D., & Kahn, B. B. (2002) · Nature · doi:10.1038/415339a · Cited by 2,053
Self-citationThe Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,694
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650
Self-citationAMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., et al. (2004) · Nature · doi:10.1038/nature02440 · Cited by 1,637
Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.009 · Cited by 1,589
Woods, A., Dickerson, K., Heath, R. B., Hong, S. P., Momcilovic, M., Johnstone, S. R., Carlson, M., & Carling, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.005 · Cited by 1,418
Research works printed but not linked: 1
- Sakamoto, 2006, Am. J. Physiol., 290, E780
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Targeting cancer with small molecule kinase inhibitors
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AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance
Garcia, D., & Shaw, R. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.032 · Cited by 2,061
AMPK: Sensing Glucose as well as Cellular Energy Status
Lin, S., & Hardie, D. G. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.10.009 · Cited by 1,198
AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome
Zhang, B. B., Zhou, G., & Li, C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.012 · Cited by 1,042
AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs
Hardie, D. G., Schaffer, B. E., & Brunet, A. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.013 · Cited by 859
Metadata
- 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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