PCK1
entrez
5105
canonical
uniprot
P35558
canonical
ensembl
ENSG00000124253
resolver
ensp
ENSP00000319814
resolver
genesymbol
PCK1
resolver
genesymbol_syn
PEPCK1
resolver
hgnc
HGNC:8724
resolver
uniprot
A8K437
resolver
uniprot
B4DT64
resolver
uniprot
Q8TCA3
resolver
uniprot
Q9UJD2
resolver
uniprot_entry
PCKGC_HUMAN
resolver
uniprot_sec
A8K437
resolver
uniprot_sec
B4DT64
resolver
uniprot_sec
Q8TCA3
resolver
uniprot_sec
Q9UJD2
resolver
activity_regulation
ACTIVITY REGULATION: Phosphoenolpyruvate carboxykinase activity is regulated by acetylation and glucose levels (PubMed:20167786, PubMed:30193097). The anaplerotic conversion of phosphoenolpyruvate to oxaloacetate is improved by PCK1 acetylation on Lys-91 (K91ac), Lys-473 (K473ac) and Lys-521 (K521ac) (By similarity). High glucose concentrations favor PCK1 anaplerotic activity by triggering acetylation on Lys-91 (K91ac). At low glucose levels, SIRT1-mediated deacetylation of Lys-91 promotes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PubMed:30193097). Phosphorylation at Ser-90 reduces the binding affinity to oxaloacetate and converts the enzyme into an atypical protein kinase using GTP as donor (PubMed:32322062). {ECO:0000250|UniProtKB:P07379, ECO:0000269|PubMed:20167786, ECO:0000269|PubMed:30193097, ECO:0000269|PubMed:32322062}.
uniprot
proteins
amino_acid_sequence
MPPQLQNGLNLSAKVVQGSLDSLPQAVREFLENNAELCQPDHIHICDGSEEENGRLLGQMEEEGILRRLKKYDNCWLALTDPRDVARIESKTVIVTQEQRDTVPIPKTGLSQLGRWMSEEDFEKAFNARFPGCMKGRTMYVIPFSMGPLGSPLSKIGIELTDSPYVVASMRIMTRMGTPVLEAVGDGEFVKCLHSVGCPLPLQKPLVNNWPCNPELTLIAHLPDRREIISFGSGYGGNSLLGKKCFALRMASRLAKEEGWLAEHMLILGITNPEGEKKYLAAAFPSACGKTNLAMMNPSLPGWKVECVGDDIAWMKFDAQGHLRAINPENGFFGVAPGTSVKTNPNAIKTIQKNTIFTNVAETSDGGVYWEGIDEPLASGVTITSWKNKEWSSEDGEPCAHPNSRFCTPASQCPIIDAAWESPEGVPIEGIIFGGRRPAGVPLVYEALSWQHGVFVGAAMRSEATAAAEHKGKIIMHDPFAMRPFFGYNFGKYLAHWLSMAQHPAAKLPKIFHVNWFRKDKEGKFLWPGFGENSRVLEWMFNRIDGKASTKLTPIGYIPKEDALNLKGLGHINMMELFSISKEFWEKEVEDIEKYLEDQVNADLPCEIEREILALKQRISQM
uniprot
proteins
disease_involvement
DISEASE: Phosphoenolpyruvate carboxykinase deficiency, cytosolic (PCKDC) [MIM:261680]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, hypoglycemia, hypotonia, hepatomegaly, hepatic dysfunction, failure to thrive, lactic acidosis, and elevated tricarboxylic acid intermediates, particularly fumarate, in urine. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.11.-
uniprot
proteins
ec_number
4.1.1.32
uniprot
proteins
function
FUNCTION: Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis (PubMed:24863970, PubMed:26971250, PubMed:28216384, PubMed:30193097). Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle (PubMed:24863970, PubMed:26971250, PubMed:28216384, PubMed:30193097). At low glucose levels, it catalyzes the cataplerotic conversion of oxaloacetate to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle (PubMed:30193097). At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate (PubMed:30193097). Acts as a regulator of formation and maintenance of memory CD8(+) T-cells: up-regulated in these cells, where it generates phosphoenolpyruvate, via gluconeogenesis (By similarity). The resultant phosphoenolpyruvate flows to glycogen and pentose phosphate pathway, which is essential for memory CD8(+) T-cells homeostasis (By similarity). In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90: phosphorylation at Ser-90 by AKT1 reduces the binding affinity to oxaloacetate and promotes an atypical serine protein kinase activity using GTP as donor (PubMed:32322062). The protein kinase activity regulates lipogenesis: upon phosphorylation at Ser-90, translocates to the endoplasmic reticulum and catalyzes phosphorylation of INSIG proteins (INSIG1 and INSIG2), thereby disrupting the interaction between INSIG proteins and SCAP and promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes (PubMed:32322062). {ECO:0000250|UniProtKB:Q9Z2V4, ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384, ECO:0000269|PubMed:30193097, ECO:0000269|PubMed:32322062}.
uniprot
proteins
mass_dalton
69195
uniprot
proteins
mutagenesis
MUTAGEN 70; /note="K->R: Abolishes acetylation and increases protein stability; when associated with R-71 and R-594."; /evidence="ECO:0000269|PubMed:20167786"; MUTAGEN 71; /note="K->R: Abolishes acetylation and increases protein stability; when associated with R-70 and R-594."; /evidence="ECO:0000269|PubMed:20167786"; MUTAGEN 90; /note="S->A: Abolished phosphorylation by AKT1, interaction with INSIG proteins (INSIG1 and INSIG2) and ability to regulate lipogenesis."; /evidence="ECO:0000269|PubMed:32322062"; MUTAGEN 90; /note="S->E: Phosphomimetic mutant, promotes the serine protein kinase activity by reducing the binding affinity to oxaloacetate."; /evidence="ECO:0000269|PubMed:32322062"; MUTAGEN 288; /note="C->S: Abolished both phosphoenolpyruvate carboxykinase and protein kinase activities."; /evidence="ECO:0000269|PubMed:32322062"; MUTAGEN 594; /note="K->R: Abolishes acetylation and increases protein stability; when associated with R-70 and R-71."; /evidence="ECO:0000269|PubMed:20167786
uniprot
proteins
pathway_participation
PATHWAY: Carbohydrate biosynthesis; gluconeogenesis. {ECO:0000269|PubMed:24863970, ECO:0000269|PubMed:26971250, ECO:0000269|PubMed:28216384, ECO:0000269|PubMed:30193097}.
uniprot
proteins
post_translational_modification
PTM: Acetylated. Lysine acetylation by p300/EP300 is increased on high glucose conditions (PubMed:20167786, PubMed:21726808, PubMed:30193097). Lysine acetylation promotes ubiquitination by UBR5 (PubMed:21726808). Acetylation is enhanced in the presence of BAG6. Deacetylated by SIRT2. Deacetylation of Lys-91 is carried out by SIRT1 and depends on PCK1 phosphorylation levels (PubMed:30193097). {ECO:0000269|PubMed:20167786, ECO:0000269|PubMed:21726808, ECO:0000269|PubMed:30193097}.; PTM: Phosphorylated in a GSK3B-mediated pathway; phosphorylation affects the efficiency of SIRT1-mediated deacetylation, and regulates PCK1 ubiquitination and degradation (PubMed:30193097). Phosphorylation at Ser-90 by AKT1 reduces the binding affinity to oxaloacetate and promotes the protein kinase activity: phosphorylated PCK1 translocates to the endoplasmic reticulum, where it phosphorylates INSIG1 and INSIG2 (PubMed:32322062). {ECO:0000269|PubMed:30193097, ECO:0000269|PubMed:32322062}.; PTM: Ubiquitination by UBR5 leads to proteasomal degradation. {ECO:0000269|PubMed:21726808}.
uniprot
proteins
protein_family
Phosphoenolpyruvate carboxykinase [GTP] family
uniprot
proteins
pubmed
11780052
uniprot
proteins
pubmed
11851336
uniprot
proteins
pubmed
14552798
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
1656199
uniprot
proteins
pubmed
17532214
uniprot
proteins
pubmed
20167786
uniprot
proteins
pubmed
21726808
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24863970
uniprot
proteins
pubmed
26971250
uniprot
proteins
pubmed
28216384
uniprot
proteins
pubmed
30193097
uniprot
proteins
pubmed
32322062
uniprot
proteins
pubmed
8325643
uniprot
proteins
pubmed
8490617
uniprot
proteins
pubmed
8547315
uniprot
proteins
sequence_length
622
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:32322062}. Endoplasmic reticulum {ECO:0000269|PubMed:32322062}. Note=Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum. {ECO:0000269|PubMed:32322062}.
uniprot
proteins