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Names & Taxonomy

Uniprot ID:: Q13131
Entry Name:: AAPK1_HUMAN
Status:: reviewed
Protein Names:: 5'-AMP-activated protein kinase catalytic subunit alpha-1 (AMPK subunit alpha-1) (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) (Tau-protein kinase PRKAA1) (EC 2.7.11.26)
Gene Names:: PRKAA1 AMPK1
Gene Names Primary:: PRKAA1
Organism:: Homo sapiens (Human)

Structure

Length:: 559
Sequence:: MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPGSHTIEFFEMCANLIKILAQ
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Cytoplasm

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. 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.
Catalytic Activity:: ATP + a protein = ADP + a phosphoprotein.
Cofactor:: COFACTOR: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Enzyme Regulation:: ENZYME REGULATION: 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 (PubMed:11602624). Selectively inhibited by compound C (6--3-pyridin-4-yl-pyyrazolo pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol.
Active Site:: ACT_SITE 150 150 Proton acceptor.
Cross Reference Drug Bank:: DB00945 DB00131 DB00171 DB00914
Gene Ontology Go:: apical plasma membrane
cytoplasm
cytosol
intracellular
nucleotide-activated protein kinase complex
nucleus
kinase activity
kinase activity
AMP-activated protein kinase activity
ATP binding
cAMP-dependent protein kinase activity
chromatin binding
histone serine kinase activity
metal ion binding
protein kinase activity
tau-protein kinase activity
activation of MAPK activity
cell cycle arrest
cellular response to ethanol
cellular response to glucose starvation
cellular response to hydrogen peroxide
cellular response to hypoxia
cellular response to nutrient levels
cellular response to prostaglandin E stimulus
cholesterol biosynthetic process
cold acclimation
fatty acid biosynthetic process
fatty acid homeostasis
fatty acid oxidation
gene expression
glucose homeostasis
glucose metabolic process
insulin receptor signaling pathway
intracellular signal transduction
lipid biosynthetic process
macroautophagy
negative regulation of apoptotic process
negative regulation of glucose import in response to insulin stimulus
negative regulation of glucosylceramide biosynthetic process
negative regulation of lipid catabolic process
negative regulation of TOR signaling
positive regulation of autophagy
positive regulation of cell proliferation
positive regulation of cholesterol biosynthetic process
positive regulation of gene expression
positive regulation of glycolytic process
positive regulation of skeletal muscle tissue development
protein heterooligomerization
protein phosphorylation
regulation of circadian rhythm
regulation of energy homeostasis
regulation of peptidyl-serine phosphorylation
regulation of transcription, DNA-templated
regulation of vesicle-mediated transport
response to activity
response to caffeine
response to camptothecin
response to gamma radiation
response to hypoxia
response to UV
rhythmic process
signal transduction
transcription initiation from RNA polymerase II promoter
Wnt signaling pathway
Gene Ontology Biological Process:: activation of MAPK activity
cell cycle arrest
cellular response to ethanol
cellular response to glucose starvation
cellular response to hydrogen peroxide
cellular response to hypoxia
cellular response to nutrient levels
cellular response to prostaglandin E stimulus
cholesterol biosynthetic process
cold acclimation
fatty acid biosynthetic process
fatty acid homeostasis
fatty acid oxidation
gene expression
glucose homeostasis
glucose metabolic process
insulin receptor signaling pathway
intracellular signal transduction
lipid biosynthetic process
macroautophagy
negative regulation of apoptotic process
negative regulation of glucose import in response to insulin stimulus
negative regulation of glucosylceramide biosynthetic process
negative regulation of lipid catabolic process
negative regulation of TOR signaling
positive regulation of autophagy
positive regulation of cell proliferation
positive regulation of cholesterol biosynthetic process
positive regulation of gene expression
positive regulation of glycolytic process
positive regulation of skeletal muscle tissue development
protein heterooligomerization
protein phosphorylation
regulation of circadian rhythm
regulation of energy homeostasis
regulation of peptidyl-serine phosphorylation
regulation of transcription, DNA-templated
regulation of vesicle-mediated transport
response to activity
response to caffeine
response to camptothecin
response to gamma radiation
response to hypoxia
response to UV
rhythmic process
signal transduction
transcription initiation from RNA polymerase II promoter
Wnt signaling pathway
Gene Ontology Molecular Function:: kinase activity
kinase activity
AMP-activated protein kinase activity
ATP binding
cAMP-dependent protein kinase activity
chromatin binding
histone serine kinase activity
metal ion binding
protein kinase activity
tau-protein kinase activity
Gene Ontology Cellular Component:: apical plasma membrane
cytoplasm
cytosol
intracellular
nucleotide-activated protein kinase complex
nucleus
Keywords:: 3D-structure
ATP-binding
Alternative splicing
Autophagy
Biological rhythms
Cholesterol biosynthesis
Cholesterol metabolism
Chromatin regulator
Complete proteome
Cytoplasm
Fatty acid biosynthesis
Fatty acid metabolism
Kinase
Lipid biosynthesis
Lipid metabolism
Magnesium
Metal-binding
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Reference proteome
Serine/threonine-protein kinase
Steroid biosynthesis
Steroid metabolism
Sterol biosynthesis
Sterol metabolism
Transcription
Transcription regulation
Transferase
Ubl conjugation
Wnt signaling pathway
Interacts With:: Q9NYB9; Q08117; O14503; O14627; Q13363-2; O95073; Q08379; Q6NT76; Q8IX15-3; P08238; Q9UKT9; Q8NBZ0; Q6A162; Q96JM7; Q5JR59; Q8IXK0; Q96PV4; Q9Y478; O43741; P54619; Q93062; Q8HWS3; Q9UFD9; Q9HAT0; Q9Y2D8; Q9NVV9; P14373; Q15654; Q9Y3Q8; Q5T124; Q9H9H4; Q8N1B4; O96006

Names & Taxonomy

Structure

Subcellular location

Function

Publication