Alternative titles; symbols
HGNC Approved Gene Symbol: PRKAA1
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38): 5:40,759,389-40,798,374 (from NCBI)
The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to play a role in protecting cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. AMPK is a heterotrimeric protein composed of 1 alpha subunit (e.g., PRKAA1), 1 beta subunit (e.g., PRKAB1; 602740), and 1 gamma subunit (e.g., PRKAG1; 602742). The catalytic alpha subunit requires phosphorylation for full activity. It is related to the S. cerevisiae Snf1 protein kinase, which is involved in the response to nutritional stress. The noncatalytic beta and gamma subunits are related to yeast proteins that interact with Snf1: the beta subunit to the Sip1/Sip2/Gal83 family of transcription regulators, and the gamma subunit to Snf4, which is thought to be an activator of Snf1 (summary by Stapleton et al., 1996).
Stapleton et al. (1996) reported the sequences of partial human liver cDNAs encoding AMPK-alpha-1.
Stapleton et al. (1996) cloned rat hypothalamus cDNAs encoding Ampk-alpha-1. By Northern blot analysis, they detected low levels of a 6-kb Ampk-alpha-1 mRNA in all rat tissues examined except testis, where a low level of a 2.4-kb transcript was observed. The predicted 548-amino acid protein has a molecular mass of approximately 63 kD by SDS-PAGE. Rat Ampk-alpha-1 and Ampk-alpha-2 (600497) have 90% amino acid sequence identity within their catalytic cores but only 61% in their C-terminal tails.
By fluorescence in situ hybridization, Stapleton et al. (1997) mapped the human AMPK-alpha-1 gene to chromosome 5p12.
Adiponectin (605441) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. Yamauchi et al. (2002) demonstrated that phosphorylation and activation of AMPK are stimulated with globular and full-length adiponectin in skeletal muscle and only with full-length adiponectin in the liver. In parallel with its activation of AMPK, adiponectin stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC1; 200350), fatty acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by a dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty acid oxidation by adiponectin occurs through activation of AMPK. Yamauchi et al. (2002) concluded that their data provided a novel paradigm, that an adipocyte-derived antidiabetic hormone, adiponectin, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
Minokoshi et al. (2004) investigated the potential role of AMP-activated protein kinase (AMPK) in the hypothalamus in the regulation of food intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited in arcuate and paraventricular hypothalamus by the anorexigenic hormone leptin (164160), and in multiple hypothalamic regions by insulin (176730), high glucose, and refeeding. A melanocortin receptor (see 155555) agonist, a potent anorexigen, decreased AMPK activity in paraventricular hypothalamus, whereas agouti-related protein (602311), an orexigen, increased AMPK activity. Melanocortin receptor signaling is required for leptin and refeeding effects of AMPK in the paraventricular hypothalamus. Dominant-negative AMPK expression in the hypothalamus was sufficient to reduce food intake and body weight, whereas constitutively active AMPK increased both. Alterations of hypothalamic AMPK activity augmented changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, Minokoshi et al. (2004) concluded that hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
Baba et al. (2006) showed that FNIP1 (610594) interacted with the alpha, beta, and gamma subunits of AMPK. FNIP1 was phosphorylated by AMPK, and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN (607273) phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR (601231) and AMPK signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.
Miller et al. (2008) showed that macrophage migration inhibitory factor (MIF; 153620), an upstream regulator of inflammation, is released in the ischemic heart, where it stimulates AMPK activation through CD74 (142790), promotes glucose uptake, and protects the heart during ischemia-reperfusion injury. Germline deletion of the Mif gene impairs ischemic AMPK signaling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischemia, functionally linking inflammation and metabolism in the heart. Miller et al. (2008) anticipated that genetic variation in MIF expression may influence the response of the human heart to ischemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.
Canto et al. (2009) demonstrated that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1 (604479). AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the PPAR-gamma coactivator 1-alpha (604517) and the FOXO1A (136533) and FOXO3A (602681) transcription factors. Canto et al. (2009) concluded that the AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biologic effects of AMPK and SIRT1 on energy metabolism.
Studying mouse fibroblasts, Lamia et al. (2009) demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome-1 (CRY1; 601933). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, Lamia et al. (2009) concluded that phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.
Bungard et al. (2010) found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B (see 609904) at ser36. AMPK recruitment and H2B ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which ser36 was substituted by alanine reduced transcription and RNA polymerase II (see 180660) association to AMPK-dependent genes, and lowered cell survival in response to stress. Bungard et al. (2010) concluded that their results placed AMPK-dependent H2B serine-36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.
AMPK is an alpha-beta-gamma heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations (summary by Oakhill et al., 2011). AMPK activation depends on phosphorylation of the alpha catalytic subunit on thr172 by kinases LKB1 (602216) or CaMKK-beta (CAMKK2; 615002), and this is promoted by AMP binding to the gamma subunit (602742). AMP sustains activity by inhibiting dephosphorylation of alpha-thr172, whereas ATP promotes dephosphorylation. Oakhill et al. (2011) found that adenosine diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated alpha-thr172 phosphorylation. However, in contrast to AMP, ADP did not directly activate phosphorylated AMPK. In this way, both ADP/ATP and AMP/ATP ratios contribute to AMPK regulation.
Salicylate, the active component of willow bark, has been in medicinal use since ancient times and has more recently been replaced by synthetic derivatives such as aspirin and salsalate. Using concentrations of salicylate reached in plasma after administration of high-dose aspirin or salsalate, Hawley et al. (2012) showed that salicylate activated AMPK. Salicylate bound AMPK at the same site as a synthetic activator to cause allosteric activation and inhibition of dephosphorylation at the activating site, thr172. In mice lacking Ampk, the effects of salicylate to increase fat utilization and to lower plasma fatty acid were lost. Hawley et al. (2012) proposed that AMPK activation explains some beneficial effects of salsalate and aspirin.
Jeon et al. (2012) demonstrated that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 (200350) and ACC2 (601557) by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty acid synthesis and increasing NADPH generation by means of fatty acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumor formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth, and solid tumor formation in vivo.
Toyama et al. (2016) found that energy-sensing AMPK is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with electron transport chain (ETC) inhibitors. Moreover, direct pharmacologic activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF; 614785), a mitochondrial outer membrane receptor for DRP1 (603850), the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.
Reviews
Sanz (2008) reviewed the structure and regulation of AMPK.
Crystal Structure
Xiao et al. (2007) reported the crystal structure of the regulatory fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate groups of AMP/ATP lie in a groove on the surface of the gamma domain, which is lined with basic residues, many of which are associated with disease-causing mutations. Structural and solution studies revealed that 2 sites on the gamma domain bind either AMP or magnesium ATP, whereas a third site contains a tightly bound AMP that does not exchange. Xiao et al. (2007) stated that their binding studies indicated that under physiologic conditions AMPK mainly exists in its inactive form in complex with magnesium ATP, which is much more abundant than AMP. Their modeling studies suggested how changes in the concentration of AMP enhance AMPK activity levels. The structure also suggested a mechanism for propagating AMP/ATP signaling whereby a phosphorylated residue from the alpha and/or beta subunits binds to the gamma subunit in the presence of AMP but not when ATP is bound.
Xiao et al. (2011) showed that ADP binding to just 1 of the 2 exchangeable AXP (AMP/ADP/ATP) binding sites on the regulatory domain of AMPK protects the enzyme from dephosphorylation, although it does not lead to allosteric activation. Their studies showed that active mammalian AMPK displays significantly tighter binding to ADP than to Mg-ATP, explaining how the enzyme is regulated under physiologic conditions where the concentration of Mg-ATP is higher than that of ADP and much higher than that of AMP. Xiao et al. (2011) determined the crystal structure of an active AMPK complex. The structure showed how the activation loop of the kinase domain is stabilized by the regulatory domain and how the kinase linker region interacts with the regulatory nucleotide-binding site that mediates protection against dephosphorylation. From their biochemical and structural data, Xiao et al. (2011) developed a model for how the energy status of a cell regulates AMPK activity.
Lin et al. (2012) reported that acetylation and deacetylation of the catalytic subunit of AMPK, PRKAA1, a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 (601241) and p300 (602700). Deacetylation of AMPK enhanced physical interaction with the upstream kinase LKB1 (602216), leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. The authors later found that the Methods section in their article was inaccurate. Because they could not reproduce all of their results, they retracted the article.
Baba, M., Hong, S.-B., Sharma, N., Warren, M. B., Nickerson, M. L., Iwamatsu, A., Esposito, D., Gillette, W. K., Hopkins, R. F., III, Hartley, J. L., Furihata, M., Oishi, S., Zhen, W., Burke, T. R., Jr., Linehan, W. M., Schmidt, L. S., Zbar, B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc. Nat. Acad. Sci. 103: 15552-15557, 2006. [PubMed: 17028174] [Full Text: https://doi.org/10.1073/pnas.0603781103]
Bungard, D., Fuerth, B. J., Zeng, P.-Y., Faubert, B., Maas, N. L., Viollet, B., Carling, D., Thompson, C. B., Jones, R. G., Berger, S. L. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329: 1201-1205, 2010. [PubMed: 20647423] [Full Text: https://doi.org/10.1126/science.1191241]
Canto, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., Auwerx, J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056-1060, 2009. [PubMed: 19262508] [Full Text: https://doi.org/10.1038/nature07813]
Hawley, S. A., Fullerton, M. D., Ross, F. A., Schertzer, J. D., Chevtzoff, C., Walker, K. J., Peggie, M. W., Zibrova, D., Green, K. A., Mustard, K. J., Kemp, B. E., Sakamoto, K., Steinberg, G. R., Hardie, D. G. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336: 918-922, 2012. [PubMed: 22517326] [Full Text: https://doi.org/10.1126/science.1215327]
Jeon, S.-M., Chandel, N. S., Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485: 661-665, 2012. [PubMed: 22660331] [Full Text: https://doi.org/10.1038/nature11066]
Lamia, K. A., Sachdeva, U. M., DiTacchio, L., Williams, E. C., Alvarez, J. G., Egan, D. F., Vasquez, D. S., Juguilon, H., Panda, S., Shaw, R. J., Thompson, C. B., Evans, R. M. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437-440, 2009. [PubMed: 19833968] [Full Text: https://doi.org/10.1126/science.1172156]
Lin, Y., Kiihl, S., Suhail, Y., Liu, S.-Y., Chou, Y., Kuang, Z., Lu, J., Khor, C. N., Lin, C.-L., Bader, J. S., Irizarry, R., Boeke, J. D. Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. Nature 482: 251-255, 2012. Note: Retraction: Nature 503: 146 only, 2013. [PubMed: 22318606] [Full Text: https://doi.org/10.1038/nature10804]
Miller, E. J., Li, J., Leng, L., McDonald, C., Atsumi, T., Bucala, R., Young, L. H. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451: 578-582, 2008. [PubMed: 18235500] [Full Text: https://doi.org/10.1038/nature06504]
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M. J., Stuck, B. J., Kahn, B. B. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569-574, 2004. [PubMed: 15058305] [Full Text: https://doi.org/10.1038/nature02440]
Oakhill, J. S., Steel, R., Chen, Z.-P., Scott, J. W., Ling, N., Tam, S., Kemp, B. E. AMPK is a direct adenylate charge-regulated protein kinase. Science 332: 1433-1435, 2011. [PubMed: 21680840] [Full Text: https://doi.org/10.1126/science.1200094]
Sanz, P. AMP-activated protein kinase: structure and regulation. Curr. Protein Pept. Sci. 9: 478-492, 2008. [PubMed: 18855699] [Full Text: https://doi.org/10.2174/138920308785915254]
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Stapleton, D., Woollatt, E., Mitchelhill, K. I., Nicholl, J. K., Fernandez, C. S., Michell, B. J., Witters, L. A., Power, D. A., Sutherland, G. R., Kemp, B. E. AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location. FEBS Lett. 409: 452-456, 1997. [PubMed: 9224708] [Full Text: https://doi.org/10.1016/s0014-5793(97)00569-3]
Toyama, E. Q., Herzig, S., Courchet, J., Lewis, T. L., Jr., Loson, O. C., Hellberg, K., Young, N. P., Chen, H., Polleux, F., Chan, D. C., Shaw, R. J. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351: 275-281, 2016. [PubMed: 26816379] [Full Text: https://doi.org/10.1126/science.aab4138]
Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T., Martin, S. R., Carling, D., Gamblin, S. J. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449: 496-500, 2007. [PubMed: 17851531] [Full Text: https://doi.org/10.1038/nature06161]
Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F., Saiu, P., Howell, S. A., Aasland, R., Martin, S. R., Carling, D., Gamblin, S. J. Structure of mammalian AMPK and its regulation by ADP. Nature 472: 230-233, 2011. [PubMed: 21399626] [Full Text: https://doi.org/10.1038/nature09932]
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P., Carling, D., Nagai, R., Kimura, S., Kahn, B. B., Kadowaki, T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Med. 8: 1288-1295, 2002. [PubMed: 12368907] [Full Text: https://doi.org/10.1038/nm788]