PCK1

This gene is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of cytosolic phosphoenolpyruvate carboxykinase deficiency. A mitochondrial isozyme of the encoded protein also has been characterized. [provided by RefSeq, Jul 2008]

Phosphoenolpyruvate Carboxykinase 1

Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis (PubMed:30193097, PubMed:24863970, PubMed:26971250, PubMed:28216384).
Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle (PubMed:30193097, PubMed:24863970, PubMed:26971250, PubMed:28216384).
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).

AgingIEA:Ensembl
Cellular response to cAMPIEA:Ensembl
Cellular response to dexamethasone stimulusManual Assertion Based On ExperimentIBA:GO_Central
Cellular response to fructose stimulusIEA:Ensembl
Cellular response to glucagon stimulusIEA:Ensembl
Cellular response to glucose stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to hypoxiaIEA:Ensembl
Cellular response to insulin stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to interleukin-1IEA:Ensembl
Cellular response to potassium ion starvationIEA:Ensembl
Cellular response to retinoic acidIEA:Ensembl
Cellular response to tumor necrosis factorIEA:Ensembl
GluconeogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Glucose homeostasisISS:BHF-UCL
Glucose metabolic processManual Assertion Based On ExperimentIMP:BHF-UCL
Glycerol biosynthetic process from pyruvateISS:BHF-UCL
Hepatocyte differentiationManual Assertion Based On ExperimentIBA:GO_Central
Oxaloacetate metabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of memory T cell differentiationISS:UniProtKB
Positive regulation of transcription from RNA polymerase II promoter in response to acidic pHIEA:Ensembl
Propionate catabolic processManual Assertion Based On ExperimentIBA:GO_Central
Regulation of lipid biosynthetic processManual Assertion Based On ExperimentIDA:UniProtKB
Response to activityIEA:Ensembl
Response to insulinManual Assertion Based On ExperimentIDA:BHF-UCL
Response to interleukin-6IEA:Ensembl
Response to lipidManual Assertion Based On ExperimentIBA:GO_Central
Response to lipopolysaccharideIEA:Ensembl
Response to methionineIEA:Ensembl
Response to starvationManual Assertion Based On ExperimentIBA:GO_Central

Cytoplasm, cytosol
Endoplasmic reticulum
Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum.

Phosphoenolpyruvate carboxykinase deficiency, cytosolic (PCKDC):
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.

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).
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).
Ubiquitination by UBR5 leads to proteasomal degradation.