AMP-activated Protein Kinase: Nature's Energy Sensor

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2011 Jul 20

PMID 21769098

Citations 184

Authors

David Carling

Faith V Mayer

Matthew J Sanders

Steven J Gamblin

Affiliations

Soon will be listed here.

Abstract

Maintaining sufficient levels of ATP (the immediate source of cellular energy) is essential for the proper functioning of all living cells. As a consequence, cells require mechanisms to balance energy demand with supply. In eukaryotic cells the AMP-activated protein kinase (AMPK) cascade has an important role in this homeostasis. AMPK is activated by a fall in ATP (concomitant with a rise in ADP and AMP), which leads to the activation of catabolic pathways and the inhibition of anabolic pathways. Here we review the role of AMPK as an energy sensor and consider the recent finding that ADP, as well as AMP, causes activation of mammalian AMPK. We also review recent progress in structural studies on phosphorylated AMPK that provides a mechanism for the regulation of AMPK in which AMP and ADP protect it against dephosphorylation. Finally, we briefly survey some of the outstanding questions concerning the regulation of AMPK.

Citing Articles

Polyphosphate: The "Dark Matter" of Bacterial Chromatin Structure.

Racki L, Freddolino L Mol Microbiol. 2025; 123(3):279-293.

PMID: 39967274 PMC: 11894788. DOI: 10.1111/mmi.15350.

Transdermal microneedle-assisted ultrasound-enhanced CRISPRa system to enable sono-gene therapy for obesity.

Li S, Yu J, Shen Y, Xiong B, Zhao D, Xu W Nat Commun. 2025; 16(1):1499.

PMID: 39929846 PMC: 11811159. DOI: 10.1038/s41467-025-56755-4.

Precise intracellular uptake and endosomal release of diverse functional mRNA payloads via glutathione-responsive nanogels.

Dabas R, Navaratnam N, Iino H, Saidjalolov S, Matile S, Carling D Mater Today Bio. 2025; 30():101425.

PMID: 39839495 PMC: 11745970. DOI: 10.1016/j.mtbio.2024.101425.

SF1-specific deletion of the energy sensor AMPKγ2 induces obesity.

Freire-Agulleiro O, Estevez-Salguero A, Ferreira V, Holleman C, Garcia-Curras J, Gonzalez-Garcia I Mol Metab. 2025; 92:102091.

PMID: 39746605 PMC: 11782900. DOI: 10.1016/j.molmet.2024.102091.

The potential mechanism of mitochondrial homeostasis in postoperative neurocognitive disorders: an in-depth review.

Ye F, Wei C, Wu A Ann Med. 2024; 56(1):2411012.

PMID: 39450938 PMC: 11514427. DOI: 10.1080/07853890.2024.2411012.

References

Sanz P, Alms G, Haystead T, Carlson M . Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1 protein kinase. Mol Cell Biol. 2000; 20(4):1321-8. PMC: 85274. DOI: 10.1128/MCB.20.4.1321-1328.2000. View

Pang T, Xiong B, Li J, Qiu B, Jin G, Shen J . Conserved alpha-helix acts as autoinhibitory sequence in AMP-activated protein kinase alpha subunits. J Biol Chem. 2006; 282(1):495-506. DOI: 10.1074/jbc.M605790200. View

Celenza J, Carlson M . A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science. 1986; 233(4769):1175-80. DOI: 10.1126/science.3526554. View

McBride A, Ghilagaber S, Nikolaev A, Grahame Hardie D . The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab. 2009; 9(1):23-34. PMC: 2642990. DOI: 10.1016/j.cmet.2008.11.008. View

Mitchelhill K, Stapleton D, Gao G, House C, Michell B, Katsis F . Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem. 1994; 269(4):2361-4. View

Garcia-Haro L, Garcia-Gimeno M, Neumann D, Beullens M, Bollen M, Sanz P . The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells. FASEB J. 2010; 24(12):5080-91. DOI: 10.1096/fj.10-166306. View

Carlson M, Osmond B, Neigeborn L, Botstein D . A suppressor of SNF1 mutations causes constitutive high-level invertase synthesis in yeast. Genetics. 1984; 107(1):19-32. PMC: 1202312. DOI: 10.1093/genetics/107.1.19. View

Hawley S, Davison M, Woods A, DAVIES S, Beri R, Carling D . Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996; 271(44):27879-87. DOI: 10.1074/jbc.271.44.27879. View

Hawley S, Selbert M, Goldstein E, EDELMAN A, Carling D, Hardie D . 5'-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J Biol Chem. 1995; 270(45):27186-91. DOI: 10.1074/jbc.270.45.27186. View

10.

Yeh L, Lee K, Kim K . Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge. J Biol Chem. 1980; 255(6):2308-14. View

11.

Carling D, Aguan K, Woods A, Verhoeven A, Beri R, Brennan C . Mammalian AMP-activated protein kinase is homologous to yeast and plant protein kinases involved in the regulation of carbon metabolism. J Biol Chem. 1994; 269(15):11442-8. View

12.

Fogarty S, Hawley S, Green K, Saner N, Mustard K, Grahame Hardie D . Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem J. 2009; 426(1):109-18. PMC: 2830670. DOI: 10.1042/BJ20091372. View

13.

Gollob M, Green M, Tang A, Gollob T, Karibe A, Ali Hassan A . Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001; 344(24):1823-31. DOI: 10.1056/NEJM200106143442403. View

14.

Stahmann N, Woods A, Carling D, Heller R . Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol. 2006; 26(16):5933-45. PMC: 1592798. DOI: 10.1128/MCB.00383-06. View

15.

Woods A, Cheung P, Smith F, Davison M, Scott J, Beri R . Characterization of AMP-activated protein kinase beta and gamma subunits. Assembly of the heterotrimeric complex in vitro. J Biol Chem. 1996; 271(17):10282-90. DOI: 10.1074/jbc.271.17.10282. View

16.

Steinberg G, Kemp B . AMPK in Health and Disease. Physiol Rev. 2009; 89(3):1025-78. DOI: 10.1152/physrev.00011.2008. View

17.

Beg Z, ALLMANN D, Gibson D . Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and wth protein fractions of rat liver cytosol. Biochem Biophys Res Commun. 1973; 54(4):1362-9. DOI: 10.1016/0006-291x(73)91137-6. View

18.

Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D . Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem. 2006; 281(43):32207-16. DOI: 10.1074/jbc.M606357200. View

19.

Neumann D, Woods A, Carling D, Wallimann T, Schlattner U . Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expr Purif. 2003; 30(2):230-7. DOI: 10.1016/s1046-5928(03)00126-8. View

20.

Stapleton D, Mitchelhill K, Gao G, Widmer J, Michell B, Teh T . Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996; 271(2):611-4. DOI: 10.1074/jbc.271.2.611. View