| IED ID | IndEnz0005001361 |
| Enzyme Type ID | lipase001361 |
| Protein Name |
5'-AMP-activated protein kinase catalytic subunit alpha-2 AMPK subunit alpha-2 EC 2.7.11.1 Acetyl-CoA carboxylase kinase ACACA kinase EC 2.7.11.27 Hydroxymethylglutaryl-CoA reductase kinase HMGCR kinase EC 2.7.11.31 |
| Gene Name | PRKAA2 AMPK AMPK2 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCASLITTLAR |
| Enzyme Length | 552 |
| Uniprot Accession Number | P54646 |
| Absorption | |
| Active Site | ACT_SITE 139; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10027" |
| Activity Regulation | ACTIVITY REGULATION: Activated by phosphorylation on Thr-172 (PubMed:15980064). Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172 (PubMed:15980064). AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172 (PubMed:15980064). ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK (PubMed:15980064). ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive (PubMed:15980064). 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. {ECO:0000269|PubMed:11602624, ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21543851, ECO:0000269|PubMed:22517326}. |
| Binding Site | BINDING 45; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:32029622}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:Q09137}; CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[acetyl-CoA carboxylase] = ADP + H(+) + O-phospho-L-seryl-[acetyl-CoA carboxylase]; Xref=Rhea:RHEA:20333, Rhea:RHEA-COMP:13722, Rhea:RHEA-COMP:13723, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.27; Evidence={ECO:0000250|UniProtKB:Q09137}; CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] = ADP + H(+) + O-phospho-L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase]; Xref=Rhea:RHEA:23172, Rhea:RHEA-COMP:13692, Rhea:RHEA-COMP:13693, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.31; Evidence={ECO:0000250|UniProtKB:Q09137}; |
| DNA Binding | |
| EC Number | 2.7.11.1; 2.7.11.27; 2.7.11.31 |
| Enzyme Function | FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357). 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 (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). 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 (PubMed:7959015). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). Involved in insulin receptor/INSR internalization (PubMed:25687571). 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 (By similarity). 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 (PubMed:11554766, PubMed:11518699, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2 (PubMed:14651849, PubMed:20160076, PubMed:21205641). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation (By similarity). Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity). {ECO:0000250|UniProtKB:Q09137, ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:25687571, ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:7959015, ECO:0000303|PubMed:17307971, ECO:0000303|PubMed:17712357}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 22..30; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Beta strand (14); Binding site (1); Chain (1); Compositional bias (1); Domain (1); Helix (22); Modified residue (4); Mutagenesis (1); Natural variant (3); Nucleotide binding (1); Region (2); Sequence conflict (3); Turn (2) |
| Keywords | 3D-structure;ATP-binding;Autophagy;Biological rhythms;Cholesterol biosynthesis;Cholesterol metabolism;Chromatin regulator;Cytoplasm;Fatty acid biosynthesis;Fatty acid metabolism;Kinase;Lipid biosynthesis;Lipid metabolism;Magnesium;Metal-binding;Nucleotide-binding;Nucleus;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Steroid biosynthesis;Steroid metabolism;Sterol biosynthesis;Sterol metabolism;Transcription;Transcription regulation;Transferase;Ubl conjugation;Wnt signaling pathway |
| Interact With | Q8IZP0-5; Q9NYB9; Q9NYB9-2; Q13155; Q9ULX6; A2BDD9; Q9Y2J4; Q9NYG5-2; Q92624; Q96B67; Q5T686; Q9P1Z2; Q13137; P0C7W6; Q9NPC3; Q00587-2; Q01850; O14627; Q8N684-3; O75638-2; A8MQ03; Q9NQM4; P50570; Q92997; Q9Y6C2-2; O95208-2; Q53EP0-3; Q6FG41; O75420; P08151; Q08379; Q9NYA3; O75791; P28799; Q6NT76; Q8IX15-3; Q13422-7; Q9UKT9; Q719H9; Q7L273; Q86T90; Q96L93-6; Q5T7B8-2; Q9BVG8; P08779; Q15323; P60411; Q96JM7; Q96JM7-2; P80188; Q9BRK4; Q13064; Q6PF18; Q9Y605; Q5JR59-3; P12524-2; Q15742; Q7Z6G3-2; Q15233-2; Q7Z3S9; Q96F24; Q86Y26; Q494U1-3; Q7Z5V6-2; Q9NQX0; Q9Y478; O43741; P54619; P31321; P41219; Q86YV0; Q93062; Q04864-2; Q8HWS3; Q9Y3C5; Q9UJW9; Q15477; Q9H6Q3; Q5JUK2; O43609; Q6ZMT1; Q15831; P15884; Q96CG3; Q08117; Q08117-2; Q15645; Q15654; Q9Y3Q8; O75385; Q9Y6N9-4; Q495M9; Q8N6Y0; Q9UK41-2; Q9H9H4; Q8N1B4; O76024; O00308; Q96BR9; Q9H0C1; Q9UDV6; Q8NF99; Q3MJ62; Q9WTK7 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BRK8}. Nucleus {ECO:0000269|PubMed:15866171}. Note=In response to stress, recruited by p53/TP53 to specific promoters. {ECO:0000269|PubMed:15866171}. |
| Modified Residue | MOD_RES 172; /note="Phosphothreonine; by LKB1 and CaMKK2"; /evidence="ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:24767988"; MOD_RES 258; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:Q09137"; MOD_RES 377; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"; MOD_RES 491; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q09137" |
| Post Translational Modification | PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q8BRK8}.; 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. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1). {ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21460634}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (11); NMR spectroscopy (1) |
| Cross Reference PDB | 2H6D; 2LTU; 2YZA; 3AQV; 4CFE; 4CFF; 4ZHX; 5EZV; 5ISO; 6B1U; 6B2E; 6BX6; |
| Mapped Pubmed ID | 10698692; 11018120; 11724780; 12067722; 12091379; 12145153; 12413941; 12427743; 12663462; 12788940; 12847291; 12941758; 14511394; 14613924; 14614828; 14693511; 14709557; 14985505; 15060529; 15231718; 15297373; 15371448; 15572372; 15579580; 16054095; 16054096; 16275868; 16483872; 16505254; 16518831; 16567511; 16598851; 16600998; 16801347; 16818670; 16943194; 16984726; 17083919; 17178807; 17179156; 17339833; 17420279; 17609368; 17721511; 17849173; 17950019; 17995453; 18195011; 18276596; 18439900; 18474106; 18614941; 18674809; 18692468; 18801964; 18974883; 18996102; 19036825; 19112161; 19170765; 19211835; 19262508; 19434633; 19440859; 19470831; 19502591; 19528236; 19531644; 19574280; 19666001; 19720831; 19723084; 19728147; 19740738; 19836452; 19913121; 19948975; 20112400; 20124121; 20167927; 20217115; 20363874; 20460103; 20538596; 20562859; 20602615; 20628086; 20647423; 20682687; 20701589; 20801214; 20821366; 20837646; 20876741; 20921139; 21062936; 21204788; 21209024; 21258367; 21318153; 21432774; 21451146; 21454505; 21474604; 21474997; 21507243; 21516116; 21673100; 21673972; 21778691; 21819378; 21825219; 22029423; 22137581; 22212710; 22284532; 22291597; 22305490; 22315316; 22359610; 22363791; 22428043; 22492524; 22514710; 22574218; 22719961; 22728651; 22821946; 22897928; 22939624; 22952994; 22972179; 22975059; 23000302; 23044421; 23152807; 23216827; 23238131; 23293026; 23298764; 23396962; 23476055; 23583109; 23685627; 23723070; 23727157; 23741428; 23747367; 23773688; 23805277; 23884233; 23935921; 23942093; 23967345; 24100028; 24189400; 24352254; 24366874; 24387300; 24389872; 24425763; 24434520; 24450630; 24467442; 24511687; 24606918; 24691558; 24746562; 24823908; 24874608; 24972246; 25061501; 25080865; 25084564; 25241761; 25241895; 25325265; 25409232; 25416956; 25497784; 25537507; 25590814; 25840010; 25846006; 25846811; 25849721; 25858560; 25961502; 26108355; 26193886; 26337566; 26351140; 26374855; 26427488; 26489410; 26496610; 26542945; 26742424; 26797128; 26804254; 26831516; 26843621; 26861281; 26893937; 26902588; 26952277; 26952388; 26997114; 26999735; 27133129; 27385336; 27494895; 27626315; 27633131; 27638620; 27687210; 27693630; 27732087; 27758765; 27779715; 27784766; 27797909; 27809416; 27887844; 28085543; 28143904; 28162974; 28183804; 28611773; 28973039; 28974016; 28994003; 29152112; 29221189; 29339542; 29399091; 29442133; 29480469; 29491475; 29654166; 29657085; 29695504; 29755474; 29799853; 29914450; 29950484; 29988028; 30011295; 30018557; 30057310; 30061832; 30270274; 30323244; 30467274; 30720062; 30864681; 31001279; 31024752; 31395901; 31404503; 31763031; 31817196; 31969821; 32029897; 32196931; 32210718; 32322334; 32323727; 32356550; 32365859; 32398698; 32511787; 32555222; 32601620; 32639656; 32649901; 32765083; 32835596; 32958832; 33194631; 33385163; 33400924; 33411680; 33482908; 33613155; 33898950; 33916175; 33919842; 34031501; 8549768; 8779952; |
| Motif | |
| Gene Encoded By | |
| Mass | 62,320 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:17989; RHEA:46608; RHEA:20333; RHEA:23172 |
| Cross Reference Brenda | 2.7.11.1;2.7.11.31; |