PRKAA1 - 5'-AMP-activated protein kinase catalytic subunit alpha-1 - human protein (Function)
 
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PRKAA1 »  5'-AMP-activated protein kinase catalytic subunit alpha-1   [ EC 2.7.11.1 ]  (AMPK subunit alpha-1)
 
Protein also known as:  Hydroxymethylglutaryl-CoA reductase kinase [EC 2.7.11.31] (HMGCR kinase).
Gene name:  PRKAA1
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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/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. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/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 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. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.  
13
  • UniProtKB
GO molecular function 
[acetyl-CoA carboxylase] kinase activitydefinition[GO:0050405]  
1
  • EC 2 GO
[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activitydefinition[GO:0047322]  
1
  • EC 2 GO
AMP-activated protein kinase activitydefinition[GO:0004679]  
1
  • UniProtKB
ATP bindingdefinition[GO:0005524]  
1
  • UniProtKB KW
cAMP-dependent protein kinase activitydefinition[GO:0004691]  
1
  • UniProtKB
Chromatin bindingdefinition[GO:0003682]  
1
  • Ortholog Curator
Histone serine kinase activitydefinition[GO:0035174]  
1
  • Ortholog Curator
Kinase bindingdefinition[GO:0019900] silver  
1
  • Ortholog Compara
Metal ion bindingdefinition[GO:0046872]  
1
  • UniProtKB KW
Protein bindingdefinition[GO:0005515]  
11
  • IntAct
  • UniProtKB
Protein C-terminus bindingdefinition[GO:0008022] silver  
1
  • Ortholog Compara
Protein kinase activitydefinition[GO:0004672]  
1
  • UniProtKB
Tau-protein kinase activitydefinition[GO:0050321]  
1
  • EC 2 GO
GO biological process 
Activation of MAPK activitydefinition[GO:0000187]  
1
  • UniProtKB
Autophagydefinition[GO:0006914]  
1
  • UniProtKB KW
Cellular response to ethanoldefinition[GO:0071361] silver  
1
  • Ortholog Compara
Cellular response to glucose starvationdefinition[GO:0042149]  
1
  • Ortholog Curator
Cellular response to hydrogen peroxidedefinition[GO:0070301] silver  
1
  • Ortholog Compara
Cellular response to hypoxiadefinition[GO:0071456] silver  
1
  • Ortholog Compara
Cellular response to nutrient levelsdefinition[GO:0031669]  
1
  • Ortholog Curator
Cholesterol biosynthetic processdefinition[GO:0006695]  
1
  • UniProtKB KW
Cold acclimationdefinition[GO:0009631] silver  
1
  • Ortholog Compara
Fatty acid biosynthetic processdefinition[GO:0006633]  
1
  • UniProtKB KW
Fatty acid homeostasisdefinition[GO:0055089]  
1
  • Ortholog Curator
Fatty acid oxidationdefinition[GO:0019395] silver  
1
  • Ortholog Compara
Glucose homeostasisdefinition[GO:0042593]  
1
  • Ortholog Curator
Glucose metabolic processdefinition[GO:0006006] silver  
1
  • Ortholog Compara
Histone-serine phosphorylationdefinition[GO:0035404] silver  
1
  • Ortholog Compara
Lipid biosynthetic processdefinition[GO:0008610]  
1
  • Ortholog Curator
Negative regulation of apoptotic processdefinition[GO:0043066]  
1
  • Ortholog Curator
Negative regulation of glucose import in response to insulin stimulusdefinition[GO:2001274] silver  
1
  • Ortholog Compara
Negative regulation of glucosylceramide biosynthetic processdefinition[GO:0046318]  
1
  • UniProtKB
Negative regulation of lipid catabolic processdefinition[GO:0050995]  
1
  • Ortholog Curator
Negative regulation of TOR signalingdefinition[GO:0032007]  
1
  • Ortholog Curator
Positive regulation of autophagydefinition[GO:0010508]  
1
  • Ortholog Curator
Positive regulation of cell proliferationdefinition[GO:0008284] silver  
1
  • Ortholog Compara
Positive regulation of cholesterol biosynthetic processdefinition[GO:0045542]  
1
  • UniProtKB
Positive regulation of gene expressiondefinition[GO:0010628]  
1
  • UniProtKB
Positive regulation of glycolytic processdefinition[GO:0045821]  
1
  • Ortholog Curator
Protein heterooligomerizationdefinition[GO:0051291] silver  
1
  • Ortholog Compara
Protein phosphorylationdefinition[GO:0006468]  
1
  • UniProtKB
Regulation of circadian rhythmdefinition[GO:0042752]  
1
  • Ortholog Curator
Regulation of energy homeostasisdefinition[GO:2000505]  
1
  • Ortholog Curator
Regulation of transcription, DNA-templateddefinition[GO:0006355]  
1
  • UniProtKB KW
Regulation of vesicle-mediated transportdefinition[GO:0060627] silver  
1
  • Ortholog Compara
Response to activitydefinition[GO:0014823] silver  
1
  • Ortholog Compara
Response to caffeinedefinition[GO:0031000] silver  
1
  • Ortholog Compara
Response to camptothecindefinition[GO:1901563] silver  
1
  • Ortholog Compara
Response to gamma radiationdefinition[GO:0010332]  
1
  • Ortholog Curator
Response to hypoxiadefinition[GO:0001666]  
1
  • UniProtKB
Response to UVdefinition[GO:0009411] silver  
1
  • Ortholog Compara
Rhythmic processdefinition[GO:0048511]  
1
  • UniProtKB KW
Signal transductiondefinition[GO:0007165]  
1
  • PINC
Transcription, DNA-templateddefinition[GO:0006351]  
1
  • UniProtKB KW
Wnt signaling pathwaydefinition[GO:0016055]  
1
  • UniProtKB KW
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reactions
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
1
  • UniProtKB
EC 2.7.11.26: ATP + [tau protein] ADP + [tau protein] phosphate.  
1
  • UniProtKB
EC 2.7.11.31: ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate.  
1
  • UniProtKB
EC 2.7.11.27: ATP + [acetyl-CoA carboxylase] ADP + [acetyl-CoA carboxylase] phosphate.  
1
  • UniProtKB
It requires the following cofactor
 Mg(2+)  
1
  • UniProtKB
It is regulated in the following manner
Activated by phosphorylation on Thr-183. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183. ADP also stimulates Thr-183 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-183, 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 (PubMed11602624). 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.  
6
  • UniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Adipocytokine signaling pathway  hsa04920+5562  
Hypertrophic cardiomyopathy (HCM)  hsa05410+5562  
Insulin signaling pathway  hsa04910+5562  
mTOR signaling pathway  hsa04150+5562  
Regulation of autophagy  hsa04140+5562  
According to Reactome, this protein belongs to the following pathways:
Regulation of AMPK activity via LKB1  REACT_21285  
Regulation of Rheb GTPase activity by AMPK  REACT_21393  
 

Keywords

Biological process 
Autophagy  definition   [KW-0072]
Biological rhythms  definition   [KW-0090]
Cholesterol biosynthesis  definition   [KW-0152]
Cholesterol metabolism  definition   [KW-0153]
Fatty acid biosynthesis  definition   [KW-0275]
Fatty acid metabolism  definition   [KW-0276]
Lipid biosynthesis  definition   [KW-0444]
Lipid metabolism  definition   [KW-0443]
Steroid biosynthesis  definition   [KW-0752]
Steroid metabolism  definition   [KW-0753]
Sterol biosynthesis  definition   [KW-0756]
Sterol metabolism  definition   [KW-1207]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Wnt signaling pathway  definition   [KW-0879]
Molecular function 
Chromatin regulator  definition   [KW-0156]
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: Protein_kinase,_AMP-activated,_alpha_1
GenomeRNAi: 5562
PRO: PR:Q13131
Chemistry
GuidetoPHARMACOLOGY: 1541