ID:AAPK2_HUMAN DESCRIPTION: RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-2; Short=AMPK subunit alpha-2; EC=2.7.11.1; AltName: Full=Acetyl-CoA carboxylase kinase; Short=ACACA kinase; EC=2.7.11.27; AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase; Short=HMGCR kinase; EC=2.7.11.31; FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CATALYTIC ACTIVITY: ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate. CATALYTIC ACTIVITY: ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate. COFACTOR: Magnesium (By similarity). ENZYME REGULATION: Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr- 172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]- 3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation. SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non- catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2. SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus. Note=In response to stress, recruited by p53/TP53 to specific promoters. DOMAIN: The AIS (autoinhibitory sequence) region some sequence similarity with the ubiquitin-associated domains and represses kinase activity. PTM: Ubiquitinated (By similarity). PTM: Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P54646
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0003682 chromatin binding GO:0004672 protein kinase activity GO:0004674 protein serine/threonine kinase activity GO:0004679 AMP-activated protein kinase activity GO:0004712 protein serine/threonine/tyrosine kinase activity GO:0005515 protein binding GO:0005524 ATP binding GO:0016301 kinase activity GO:0016740 transferase activity GO:0035174 histone serine kinase activity GO:0046872 metal ion binding GO:0047322 [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity GO:0050405 [acetyl-CoA carboxylase] kinase activity
Biological Process: GO:0006325 chromatin organization GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006468 protein phosphorylation GO:0006629 lipid metabolic process GO:0006631 fatty acid metabolic process GO:0006633 fatty acid biosynthetic process GO:0006694 steroid biosynthetic process GO:0006695 cholesterol biosynthetic process GO:0006914 autophagy GO:0006950 response to stress GO:0007050 cell cycle arrest GO:0007165 signal transduction GO:0008202 steroid metabolic process GO:0008203 cholesterol metabolic process GO:0008610 lipid biosynthetic process GO:0010468 regulation of gene expression GO:0010508 positive regulation of autophagy GO:0010629 negative regulation of gene expression GO:0014850 response to muscle activity GO:0016055 Wnt signaling pathway GO:0016126 sterol biosynthetic process GO:0016236 macroautophagy GO:0016239 positive regulation of macroautophagy GO:0016241 regulation of macroautophagy GO:0016310 phosphorylation GO:0031669 cellular response to nutrient levels GO:0032007 negative regulation of TOR signaling GO:0034599 cellular response to oxidative stress GO:0035404 histone-serine phosphorylation GO:0035556 intracellular signal transduction GO:0035690 cellular response to drug GO:0042149 cellular response to glucose starvation GO:0042304 regulation of fatty acid biosynthetic process GO:0042593 glucose homeostasis GO:0042752 regulation of circadian rhythm GO:0043066 negative regulation of apoptotic process GO:0045821 positive regulation of glycolytic process GO:0048511 rhythmic process GO:0055089 fatty acid homeostasis GO:0070507 regulation of microtubule cytoskeleton organization GO:0071277 cellular response to calcium ion GO:0071333 cellular response to glucose stimulus GO:0071380 cellular response to prostaglandin E stimulus GO:0097009 energy homeostasis GO:1903829 positive regulation of cellular protein localization GO:1904428 negative regulation of tubulin deacetylation GO:2000758 positive regulation of peptidyl-lysine acetylation
AK314011 - Homo sapiens cDNA, FLJ94666, highly similar to Homo sapiens protein kinase, AMP-activated, alpha 2 catalyticsubunit (PRKAA2), mRNA. U06454 - Human AMP-activated protein kinase (hAMPK) mRNA, complete cds. BC069680 - Homo sapiens protein kinase, AMP-activated, alpha 2 catalytic subunit, mRNA (cDNA clone MGC:97288 IMAGE:7262537), complete cds. BC069740 - Homo sapiens protein kinase, AMP-activated, alpha 2 catalytic subunit, mRNA (cDNA clone MGC:97300 IMAGE:7262549), complete cds. BC069823 - Homo sapiens protein kinase, AMP-activated, alpha 2 catalytic subunit, mRNA (cDNA clone MGC:97312 IMAGE:7262561), complete cds. KJ905279 - Synthetic construct Homo sapiens clone ccsbBroadEn_14777 PRKAA2 gene, encodes complete protein. EF056019 - Homo sapiens AMP-activated alpha 2 subunit (PRKAA2) mRNA, complete cds. FJ200485 - Homo sapiens AMP-activated protein kinase alpha-2 subunit variant 2 (PRKAA2) mRNA, complete cds. FJ200486 - Homo sapiens AMP-activated protein kinase alpha-2 subunit variant 3 (PRKAA2) mRNA, complete cds. HQ628625 - Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform D (AMPK alpha 2) mRNA, complete cds, alternatively spliced. JD457931 - Sequence 438955 from Patent EP1572962. JD449861 - Sequence 430885 from Patent EP1572962. JD563486 - Sequence 544510 from Patent EP1572962. JD548456 - Sequence 529480 from Patent EP1572962. JD262835 - Sequence 243859 from Patent EP1572962. JD563870 - Sequence 544894 from Patent EP1572962. JD352361 - Sequence 333385 from Patent EP1572962. JD318700 - Sequence 299724 from Patent EP1572962. JD359355 - Sequence 340379 from Patent EP1572962. JD481176 - Sequence 462200 from Patent EP1572962. JD288979 - Sequence 270003 from Patent EP1572962. JD228662 - Sequence 209686 from Patent EP1572962. JD259095 - Sequence 240119 from Patent EP1572962. JD175729 - Sequence 156753 from Patent EP1572962. JD332021 - Sequence 313045 from Patent EP1572962. JD531481 - Sequence 512505 from Patent EP1572962. BC043195 - Homo sapiens cDNA clone IMAGE:5288757.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_chrebpPathway - ChREBP regulation by carbohydrates and cAMP h_leptinPathway - Reversal of Insulin Resistance by Leptin
Reactome (by CSHL, EBI, and GO)
Protein P54646 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
