AMP‐activated Protein Kinase (AMPK)

Abstract

AMP‐activated protein kinase (AMPK) is a heterotrimeric protein kinase complex that is expressed in essentially all eukaryotes. It acts as a sensor of cellular energy status by monitoring the levels of adenine nucleotides, especially adenosine‐5′‐monophosphate (AMP), adenosine‐5′‐diphosphate (ADP) and adenosine‐5′‐triphosphate (ATP). When activated by falling cellular energy status, AMPK acts to restore energy balance by switching on ATP‐producing catabolic pathways (such as the uptake and oxidation of glucose and fatty acids), while switching off any energy‐requiring processes (such as biosynthesis, cell growth and division) that are not essential for short‐term cell survival. AMPK is also regulated by hormones and cytokines that control energy balance at the whole body level, and it is involved in several common disorders in humans, including type 2 diabetes and cancer.

Key Concepts:

  • An analogy can be drawn between cellular ATP and ADP and the chemicals in a rechargeable battery.

  • Catabolism (and/or photosynthesis) ‘charges the cellular battery’ by converting ADP to ATP.

  • Almost all other cellular processes require energy and are driven by conversion of ATP to ADP, thus ‘flattening the battery’.

  • All living cells must maintain a balance between ATP production and ATP consumption at all times, thus maintaining energy homoeostasis.

  • In eukaryotic cells, one key system that maintains energy homoeostasis is the AMP‐activated protein kinase (AMPK).

  • The gamma subunit of AMPK binds AMP, ADP and ATP, and increases in AMP:ATP and ADP:ATP ratios (signals of compromised cellular energy status) activate AMPK.

  • Once activated, AMPK switches on alternate catabolic pathways that generate ATP, while switching off energy‐consuming processes, thus conserving ATP.

  • Although it appears to have evolved to maintain energy homoeostasis in a cell‐autonomous manner, in multicellular eukaryotes AMPK is also regulated by hormones and cytokines that regulate whole body energy balance.

  • AMPK is a key drug target in the treatment of common human disorders such as type 2 diabetes, cancer and inflammatory disorders.

Keywords: energy balance; protein kinase; metabolism; AMP; ADP; ATP

Figure 1.

Schematic showing role of AMPK in the regulation of cellular energy balance. Catabolism normally maintains a high ratio of ATP:ADP in the cell (typically 10:1). Inhibition of catabolism (e.g. starvation for glucose or oxygen), or acceleration of ATP consumption (e.g. muscle contraction) would cause an increase in the ADP:ATP ratio that is converted by the enzyme adenylate kinase into an even larger rise in AMP:ATP. Rising AMP coupled with falling ATP switches on the AMPK system, which then activates alternate catabolic pathways and switches off ATP‐consuming processes to restore energy homeostasis. ADP, adenosine‐5′‐diphosphate; AMP, adenosine‐5′‐monophosphate; AMPK, AMP‐activated protein kinase; ATP, adenosine‐5′‐triphosphate.

Figure 2.

Structure of the human AMPK α2β1γ1 complex. The model contains all of the major globular domains, although some of the linking peptides were not fully resolved. For the protein itself, only the course of the polypeptide backbone is shown in ‘cartoon’ view. Bound ligands (3 molecules of AMP, the pharmacological activator ‘991’ and the kinase inhibitor staurosporine), and the phosphorylated side chain of Thr‐172, are represented in ‘sphere’ view, with carbon green, nitrogen blue, oxygen red, phosphorus orange and hydrogen omitted. The region of the β1 subunit N‐terminal to the CBM, and the linker between CBM and the C‐terminal domain, were not resolved. The extended linker peptide between the AID and the C‐terminal domain of the α subunit was partially resolved, and can be seen (in yellow) wrapping around the side of the γ subunit facing the viewer. α‐AID, α‐subunit autoinhibitory domain; CBM, carbohydrate binding module. The image was created using published atomic coordinates by Xiao et al. (). © Nature Publishing Group.

Figure 3.

Summary of metabolic stresses, drugs and cytokines that regulate AMP‐activated protein kinase (AMPK).

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References

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Further Reading

Arad M, Seidman CE and Seidman JG (2007) AMP‐activated protein kinase in the heart: role during health and disease. Circulation Research 100: 474–488.

Hardie DG (2013) AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62: 2164–2172.

Hardie DG and Ashford ML (2013) AMPK: regulating energy balance at the cellular and whole body levels. Physiology (Bethesda) 29: 99–107.

Hardie DG, Ross FA and Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature ReviewsMolecular Cell Biology 13: 251–262.

O'Neill LA and Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo‐starvation. Nature 493: 346–355.

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Hardie, D Grahame(Jul 2014) AMP‐activated Protein Kinase (AMPK). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021030.pub2]