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Review
. 2014 Dec;276(6):543-59.
doi: 10.1111/joim.12268. Epub 2014 May 27.

AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease

D Grahame Hardie  1
Affiliations
Review

AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease

D Grahame Hardie. J Intern Med. 2014 Dec.

Abstract

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that regulates cellular and whole-body energy balance. A recently reported crystal structure has illuminated the complex regulatory mechanisms by which AMP and ADP cause activation of AMPK, involving phosphorylation by the upstream kinase LKB1. Once activated by falling cellular energy status, AMPK activates catabolic pathways that generate ATP whilst inhibiting anabolic pathways and other cellular processes that consume ATP. A role of AMPK is implicated in many human diseases. Mutations in the γ2 subunit cause heart disease due to excessive glycogen storage in cardiac myocytes, leading to ventricular pre-excitation. AMPK-activating drugs reverse many of the metabolic defects associated with insulin resistance, and recent findings suggest that the insulin-sensitizing effects of the widely used antidiabetic drug metformin are mediated by AMPK. The upstream kinase LKB1 is a tumour suppressor, and AMPK may exert many of its antitumour effects. AMPK activation promotes the oxidative metabolism typical of quiescent cells, rather than the aerobic glycolysis observed in tumour cells and cells involved in inflammation, explaining in part why AMPK activators have both antitumour and anti-inflammatory effects. Salicylate (the major in vivo metabolite of aspirin) activates AMPK, and this could be responsible for at least some of the anticancer and anti-inflammatory effects of aspirin. In addition to metformin and salicylates, novel drugs that modulate AMPK are likely to enter clinical trials soon. Finally, AMPK may be involved in viral infection: downregulation of AMPK during hepatitis C virus infection appears to be essential for efficient viral replication.

Keywords: Wolff-Parkinson-White syndrome; biochemistry; cancer; cell biology; metformin; type 2 diabetes mellitus.

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Figures

Figure 1
Figure 1. Structure of the heterotrimeric AMPK complex.
The linear layout of the domains is shown at the top, and a three dimensional model of a human α2β1γ1 complex (created in MacPyMol from the RCSB ProteinDataBank entry 4CFE [22]) at the bottom, using similar color coding. From the view at the bottom, the complex can be seen to be divided into two rather separate regions, the “catalytic module” at top left, and the “nucleotide-binding module” at bottom right, with Thr172 partially exposed in the narrow cleft between them. The activators AMP (only shown in sites 1 and 3) and 991, the inhibitor staurosporine, and the side chain of Thr172 are in “sphere” view with C atoms in green, O in red, and N in blue (H omitted). The extended linker that connects the α-AID and the α-CTD, which wraps around one face of the γ subunit, is in “stick” view in deep blue color. All other domains are in “cartoon” view with α-helices represented as cylinders and β-strands as ribbons. The “ST loop” a regulatory region referred to in the text, was not resolved in this structure, but its approximate location is shown by a black dashed line.
Figure 2
Figure 2. Summary of selected protein targets and processes downstream of AMPK.
A green arrow signifies activation, and a red line with a cross-bar signifies inhibition. Note that if AMPK inhibits a protein that in turn inhibits a downstream process, (two successive red lines with cross-bars) then the overall process (e.g. glucose uptake, fatty acid oxidation) will be activated. A question mark next to a protein signifies that it is not certain that the protein is a direct target for AMPK.
Figure 3
Figure 3. Model for acute activation of glucose transport in muscle by AMPK.
In the unphosphorylated form, the protein TBC1D1 retains GLUT4 at intracellular sites because its Rab-GAP domain promotes the inactive GDP-bound state of members of the Rab family of small G proteins. AMPK phosphorylates TBC1D1 at Ser237 near the PTB1 domain, while Akt (and perhaps also AMPK?) phosphorylates Thr596 near PTB2. This dual phosphorylation promotes the binding of 14:3:3 proteins, abundant dimeric proteins containing two symmetrical pockets that bind to phosphorylated peptides, which is proposed to inhibit the Rab-GAP activity of TBC1D1. The functions of the two phosphotyrosine-binding (PTB) domains of TBC1D1 remain unclear.
Figure 4
Figure 4. Acute activation of fatty acid oxidation and inhibition of fatty acid synthesis by AMPK.
AMPK phosphorylates both isoforms ACC1 and ACC2 at equivalent sites (Ser80 and Ser221 in human ACC1 and ACC2 respectively), causing their inactivation. This lowers malonyl-CoA, a key intermediate in fatty acid synthesis that is also an inhibitor of carnitine palmitoyl transferase-1 (CPT1). CPT1 is involved in uptake of fatty acids into mitochondria, where they are oxidized to generate ATP. It was thought that ACC1 produced the pool of malonyl-CoA involved in fatty acid synthesis, and ACC2 a separate pool of malonyl-CoA that regulates CPT1 [117], but recent results suggest that these two pools cannot be completely distinct [77].
Figure 5
Figure 5. Growth factors activate, whereas energy stress and AMPK inactivate, the mechanistic target-of-rapamycin complex 1 (mTORC1).
mTORC1 is a large multiprotein complex containing mTOR and Raptor, which phosphorylates and activates S6 kinase-1, an activator of protein synthesis, and phosphorylates and inactivates initiation factor 4E-binding protein-1 (4E-BP1), an inhibitor of protein synthesis. Binding of the active GTP-bound form of the small G protein Rheb recruits mTORC1 to the lysosome, where it is activated. Growth factors activate the protein kinase B/Akt pathway and the Erk pathway, and both of those protein kinases phosphorylate the TSC2 component of the TSC1:TSC2 complex, inhibiting its Rheb-GAP activity and thus activating mTORC1. PKB/Akt also phosphorylates PRAS40, relieving its inhibitory effect on mTORC1. On the other hand AMPK, activated in response to energy stress, phosphorylates TSC2, enhancing its Rheb-GAP activity, as well as Raptor, with both effects inhibiting mTORC1.
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