PRKAA1
entrez
5562
canonical
uniprot
Q13131
canonical
ensembl
ENSG00000132356
resolver
ensp
ENSP00000296800
resolver
ensp
ENSP00000346148
resolver
ensp
ENSP00000380317
resolver
genesymbol
PRKAA1
resolver
genesymbol_syn
AMPK1
resolver
hgnc
HGNC:9376
resolver
uniprot
A8MTQ6
resolver
uniprot
B2R7E1
resolver
uniprot
O00286
resolver
uniprot
Q5D0E1
resolver
uniprot
Q86VS1
resolver
uniprot
Q9UNQ4
resolver
uniprot_entry
AAPK1_HUMAN
resolver
uniprot_sec
A8MTQ6
resolver
uniprot_sec
B2R7E1
resolver
uniprot_sec
O00286
resolver
uniprot_sec
Q5D0E1
resolver
uniprot_sec
Q86VS1
resolver
uniprot_sec
Q9UNQ4
resolver
activity_regulation
ACTIVITY REGULATION: Activated by phosphorylation on Thr-183 by STK11/LKB1 (PubMed:14976552). Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183 (PubMed:15980064, PubMed:16054095, PubMed:21680840). AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183 (PubMed:15980064, PubMed:16054095, PubMed:21680840). ADP also stimulates Thr-183 phosphorylation, without stimulating already phosphorylated AMPK (PubMed:15980064, PubMed:16054095, PubMed:21680840). ATP promotes dephosphorylation of Thr-183, rendering the enzyme inactive (PubMed:15980064, PubMed:16054095, PubMed:21680840). Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP (PubMed:15980064, PubMed:16054095, PubMed:21680840). Inhibited by modified adenosine monophosphate (AMP) N(6)-methyl-AMP (m6AMP), N(6),N(6)-dimethyl-AMP (m6,6AMP) and N(6)-isopentenyl-AMP (i6AMP) (By similarity). 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 (PubMed:11602624). However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Activated by lithocholic acid in response to calorie restriction: activation is mediated by the AXIN1-STK11/LKB1 axis, which promotes phosphorylation by STK11/LKB1, leading to mTORC1 inhibition (By similarity). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (PubMed:17307971, PubMed:17712357). Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol (PubMed:17307971, PubMed:17712357). {ECO:0000250|UniProtKB:Q5EG47, ECO:0000269|PubMed:11602624, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:16054095, ECO:0000269|PubMed:21680840, ECO:0000303|PubMed:17307971, ECO:0000303|PubMed:17712357}.
uniprot
proteins
amino_acid_sequence
MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPGSHTIEFFEMCANLIKILAQ
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
ec_number
2.7.11.26
uniprot
proteins
ec_number
2.7.11.31
uniprot
proteins
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, PubMed:24563466, PubMed:31492851, PubMed:37821951, PubMed:40233740). 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 (By similarity). 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). 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:11518699, PubMed:11554766, 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 FNIP1, TSC2, RPTOR, WDR24 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:18439900, PubMed:20160076, PubMed:21205641). Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation (PubMed:36732624). In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes (PubMed:37079666). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process, it also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). 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 has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). Regulates hepatic lipogenesis. Activated via SIRT3, represses sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. Upon stress, regulates mitochondrial fragmentation through phosphorylation of MTFR1L (PubMed:36367943). Phosphorylates ALDH7A1 in response to cellular stress, such as hypoxia or ferroptotic stress, promoting ALDH7A1 recruitment to membranes (PubMed:31492851, PubMed:40233740). {ECO:0000250|UniProtKB:P54645, ECO:0000250|UniProtKB:Q5EG47, 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:18439900, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:24563466, ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:31492851, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:36367943, ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666, ECO:0000269|PubMed:37821951, ECO:0000269|PubMed:40233740, ECO:0000303|PubMed:17307971, ECO:0000303|PubMed:17712357}.
uniprot
proteins
mass_dalton
64009
uniprot
proteins
mutagenesis
MUTAGEN 307; /note="V->G,Q: Activates the kinase activity."; /evidence="ECO:0000269|PubMed:17088252
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q5EG47}.; PTM: Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK. Dephosphorylated by PPM1A and PPM1B. {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:16054095, ECO:0000269|PubMed:21460634}.; PTM: Glycosylated; O-GlcNAcylated by OGT, promoting the AMP-activated protein kinase (AMPK) activity. {ECO:0000269|PubMed:24563466}.
uniprot
proteins
protein_family
CAMK Ser/Thr protein kinase family
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
SNF1 subfamily
uniprot
proteins
pubmed
11042152
uniprot
proteins
pubmed
11518699
uniprot
proteins
pubmed
11554766
uniprot
proteins
pubmed
11602624
uniprot
proteins
pubmed
12519745
uniprot
proteins
pubmed
14651849
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14976552
uniprot
proteins
pubmed
15372022
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15866171
uniprot
proteins
pubmed
15980064
uniprot
proteins
pubmed
16054095
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17028174
uniprot
proteins
pubmed
17088252
uniprot
proteins
pubmed
17307971
uniprot
proteins
pubmed
17486097
uniprot
proteins
pubmed
17711846
uniprot
proteins
pubmed
17712357
uniprot
proteins
pubmed
18088087
uniprot
proteins
pubmed
18184930
uniprot
proteins
pubmed
18220336
uniprot
proteins
pubmed
18403135
uniprot
proteins
pubmed
18439900
uniprot
proteins
pubmed
18663353
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20074060
uniprot
proteins
pubmed
20160076
uniprot
proteins
pubmed
21205641
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21460634
uniprot
proteins
pubmed
21680840
uniprot
proteins
pubmed
23088624
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24563466
uniprot
proteins
pubmed
28561066
uniprot
proteins
pubmed
31492851
uniprot
proteins
pubmed
32029622
uniprot
proteins
pubmed
33606008
uniprot
proteins
pubmed
34077757
uniprot
proteins
pubmed
36367943
uniprot
proteins
pubmed
36732624
uniprot
proteins
pubmed
37079666
uniprot
proteins
pubmed
37821951
uniprot
proteins
pubmed
40233740
uniprot
proteins
pubmed
8557660
uniprot
proteins
pubmed
9857077
uniprot
proteins
sequence_length
559
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:37821951}. Nucleus {ECO:0000269|PubMed:15866171}. Late endosome {ECO:0000250|UniProtKB:Q5EG47}. Note=In response to stress, recruited by p53/TP53 to specific promoters. Translocates to late endosomes in response to calorie restriction (By similarity). {ECO:0000250|UniProtKB:Q5EG47, ECO:0000269|PubMed:15866171}.
uniprot
proteins