PCK1 (phosphoenolpyruvate carboxykinase 1)

Gene

• Entrez ID: 5105
• Gene name: Phosphoenolpyruvate carboxykinase 1
• Gene symbol: PCK1
• Synonyms: PCKDC, PEPCK-C, PEPCK1, PEPCKC
• Chromosome: 20
• Chromosome location: 20q13.31
• Summary: 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]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs147120329	C>T	Conflicting-interpretations-of-pathogenicity	5 prime UTR variant, missense variant, coding sequence variant
rs148684857	G>A	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Missense variant, coding sequence variant
rs201186470	G>A	Pathogenic, uncertain-significance	Missense variant, coding sequence variant
rs373906233	G>A	Likely-pathogenic	Coding sequence variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT054920	hsa-miR-33b-5p	Luciferase reporter assay, qRT-PCR	23716591
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	24906430
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	23824327
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	23313552
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	22927820
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	27418678
MIRT607460	hsa-miR-1277-5p	HITS-CLIP	28735896
MIRT607461	hsa-miR-190a-3p	HITS-CLIP	24906430
MIRT607461	hsa-miR-190a-3p	HITS-CLIP	23824327
MIRT607461	hsa-miR-190a-3p	HITS-CLIP	23313552
MIRT607461	hsa-miR-190a-3p	HITS-CLIP	22927820
MIRT607461	hsa-miR-190a-3p	HITS-CLIP	27418678
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	24906430
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	23824327
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	23313552
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	22927820
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	27418678
MIRT607462	hsa-miR-5011-5p	HITS-CLIP	28735896
MIRT607463	hsa-miR-4789-3p	HITS-CLIP	24906430
MIRT607463	hsa-miR-4789-3p	HITS-CLIP	23824327
MIRT607463	hsa-miR-4789-3p	HITS-CLIP	23313552
MIRT607463	hsa-miR-4789-3p	HITS-CLIP	22927820
MIRT607463	hsa-miR-4789-3p	HITS-CLIP	27418678
MIRT607464	hsa-miR-8485	HITS-CLIP	24906430
MIRT607464	hsa-miR-8485	HITS-CLIP	23824327
MIRT607464	hsa-miR-8485	HITS-CLIP	23313552
MIRT607464	hsa-miR-8485	HITS-CLIP	22927820
MIRT607464	hsa-miR-8485	HITS-CLIP	27418678
MIRT620245	hsa-miR-4482-3p	HITS-CLIP	23824327
MIRT620246	hsa-miR-7159-3p	HITS-CLIP	23824327
MIRT620247	hsa-miR-627-3p	HITS-CLIP	23824327
MIRT620248	hsa-miR-330-3p	HITS-CLIP	23824327
MIRT620249	hsa-miR-7151-5p	HITS-CLIP	23824327
MIRT620250	hsa-miR-3163	HITS-CLIP	23824327
MIRT620251	hsa-miR-5582-3p	HITS-CLIP	23824327
MIRT620252	hsa-miR-548f-3p	HITS-CLIP	23824327
MIRT620253	hsa-miR-548e-3p	HITS-CLIP	23824327
MIRT620254	hsa-miR-548az-3p	HITS-CLIP	23824327
MIRT620255	hsa-miR-548ar-3p	HITS-CLIP	23824327
MIRT620256	hsa-miR-548a-3p	HITS-CLIP	23824327
MIRT626357	hsa-miR-8064	HITS-CLIP	23824327
MIRT626357	hsa-miR-8064	HITS-CLIP	22927820
MIRT626357	hsa-miR-8064	HITS-CLIP	27418678
MIRT639564	hsa-miR-1185-2-3p	HITS-CLIP	23824327
MIRT639564	hsa-miR-1185-2-3p	HITS-CLIP	23313552
MIRT639564	hsa-miR-1185-2-3p	HITS-CLIP	27418678
MIRT639564	hsa-miR-1185-2-3p	HITS-CLIP	28735896
MIRT639565	hsa-miR-1185-1-3p	HITS-CLIP	23824327
MIRT639565	hsa-miR-1185-1-3p	HITS-CLIP	23313552
MIRT639565	hsa-miR-1185-1-3p	HITS-CLIP	27418678
MIRT639565	hsa-miR-1185-1-3p	HITS-CLIP	28735896
MIRT639566	hsa-let-7f-2-3p	HITS-CLIP	23824327
MIRT639566	hsa-let-7f-2-3p	HITS-CLIP	23313552
MIRT639566	hsa-let-7f-2-3p	HITS-CLIP	27418678
MIRT639566	hsa-let-7f-2-3p	HITS-CLIP	28735896
MIRT647682	hsa-miR-548t-3p	HITS-CLIP	23824327
MIRT647683	hsa-miR-548ap-3p	HITS-CLIP	23824327
MIRT647684	hsa-miR-548aa	HITS-CLIP	23824327
MIRT733095	hsa-miR-26a-1-3p	Luciferase reporter assay, qRT-PCR, Western blot	25961460
MIRT790091	hsa-miR-129-5p	HITS-CLIP	28735896
MIRT790094	hsa-miR-1297	HITS-CLIP	28735896
MIRT790203	hsa-miR-26a-5p	HITS-CLIP	28735896
MIRT790204	hsa-miR-26b-5p	HITS-CLIP	28735896
MIRT790321	hsa-miR-3650	HITS-CLIP	28735896
MIRT790465	hsa-miR-4465	HITS-CLIP	28735896
MIRT790781	hsa-miR-5697	HITS-CLIP	28735896

Transcription factors

Transcription factor	Regulation	Reference
ATF2	Activation	12453892
CEBPA	Unknown	12237288
SP1	Activation	14744869
SREBF1	Repression	14744869

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000287	Function	Magnesium ion binding	IDA	11851336
GO:0004613	Function	Phosphoenolpyruvate carboxykinase (GTP) activity	IBA	21873635
GO:0004613	Function	Phosphoenolpyruvate carboxykinase (GTP) activity	IDA	30193097, 32322062
GO:0004613	Function	Phosphoenolpyruvate carboxykinase (GTP) activity	IMP	26971250
GO:0004613	Function	Phosphoenolpyruvate carboxykinase (GTP) activity	ISS
GO:0004613	Function	Phosphoenolpyruvate carboxykinase (GTP) activity	TAS
GO:0005525	Function	GTP binding	IDA	11851336
GO:0005737	Component	Cytoplasm	ISS
GO:0005739	Component	Mitochondrion	IBA	21873635
GO:0005783	Component	Endoplasmic reticulum	IDA	32322062
GO:0005829	Component	Cytosol	IBA	21873635
GO:0005829	Component	Cytosol	IDA	32322062
GO:0005829	Component	Cytosol	TAS
GO:0006006	Process	Glucose metabolic process	IMP	14764811
GO:0006094	Process	Gluconeogenesis	IBA	21873635
GO:0006094	Process	Gluconeogenesis	IEA
GO:0006094	Process	Gluconeogenesis	IMP	26971250
GO:0006094	Process	Gluconeogenesis	ISS
GO:0006094	Process	Gluconeogenesis	TAS
GO:0006107	Process	Oxaloacetate metabolic process	IDA	30193097
GO:0007568	Process	Aging	IEA
GO:0014823	Process	Response to activity	IEA
GO:0018105	Process	Peptidyl-serine phosphorylation	IDA	32322062
GO:0019003	Function	GDP binding	IEA
GO:0019543	Process	Propionate catabolic process	IBA	21873635
GO:0030145	Function	Manganese ion binding	IBA	21873635
GO:0030145	Function	Manganese ion binding	IDA	11851336
GO:0031406	Function	Carboxylic acid binding	IDA	11851336
GO:0032496	Process	Response to lipopolysaccharide	IEA
GO:0032868	Process	Response to insulin	IDA	14764811
GO:0032869	Process	Cellular response to insulin stimulus	IBA	21873635
GO:0032869	Process	Cellular response to insulin stimulus	IDA	32322062
GO:0033993	Process	Response to lipid	IBA	21873635
GO:0042593	Process	Glucose homeostasis	ISS
GO:0042594	Process	Response to starvation	IBA	21873635
GO:0043382	Process	Positive regulation of memory T cell differentiation	ISS
GO:0046327	Process	Glycerol biosynthetic process from pyruvate	IBA	21873635
GO:0046327	Process	Glycerol biosynthetic process from pyruvate	ISS
GO:0046890	Process	Regulation of lipid biosynthetic process	IDA	32322062
GO:0051365	Process	Cellular response to potassium ion starvation	IEA
GO:0061402	Process	Positive regulation of transcription from RNA polymerase II promoter in response to acidic pH	IEA
GO:0070062	Component	Extracellular exosome	HDA	19056867
GO:0070365	Process	Hepatocyte differentiation	IBA	21873635
GO:0070741	Process	Response to interleukin-6	IEA
GO:0071300	Process	Cellular response to retinoic acid	IEA
GO:0071320	Process	Cellular response to cAMP	IEA
GO:0071332	Process	Cellular response to fructose stimulus	IEA
GO:0071333	Process	Cellular response to glucose stimulus	IBA	21873635
GO:0071333	Process	Cellular response to glucose stimulus	IDA	30193097
GO:0071347	Process	Cellular response to interleukin-1	IEA
GO:0071356	Process	Cellular response to tumor necrosis factor	IEA
GO:0071377	Process	Cellular response to glucagon stimulus	IEA
GO:0071456	Process	Cellular response to hypoxia	IEA
GO:0071549	Process	Cellular response to dexamethasone stimulus	IBA	21873635
GO:0106264	Function	Protein serine kinase activity (using GTP as donor)	IDA	32322062
GO:1904640	Process	Response to methionine	IEA

Other IDs

• MIM: 614168
• HGNC: 8724
• e!Ensembl: ENSG00000124253

Protein

• UniProt ID: P35558
• Protein name: Phosphoenolpyruvate carboxykinase, cytosolic [GTP] (PEPCK-C) (EC 4.1.1.32) (Serine-protein kinase PCK1) (EC 2.7.11.-)
• Protein function: 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).
• PDB: 1KHB, 1KHE, 1KHF, 1KHG, 1M51, 1NHX, 2GMV
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF17297	PEPCK_N	29 → 256	Phosphoenolpyruvate carboxykinase N-terminal domain	Domain
  PF00821	PEPCK_GTP	260 → 619	Phosphoenolpyruvate carboxykinase C-terminal P-loop domain	Domain

• Sequence:

  MPPQLQNGLNLSAKVVQGSLDSLPQAVREFLENNAELCQPDHIHICDGSEEENGRLLGQM
  EEEGILRRLKKYDNCWLALTDPRDVARIESKTVIVTQEQRDTVPIPKTGLSQLGRWMSEE
  DFEKAFNARFPGCMKGRTMYVIPFSMGPLGSPLSKIGIELTDSPYVVASMRIMTRMGTPV
  LEAVGDGEFVKCLHSVGCPLPLQKPLVNNWPCNPELTLIAHLPDRREIISFGSGYGGNSL
  LGKKCFALRMASRLAKEEGWLAEHMLILGITNPEGEKKYLAAAFPSACGKTNLAMMNPSL
  PGWKVECVGDDIAWMKFDAQGHLRAINPENGFFGVAPGTSVKTNPNAIKTIQKNTIFTNV
  AETSDGGVYWEGIDEPLASGVTITSWKNKEWSSEDGEPCAHPNSRFCTPASQCPIIDAAW
  ESPEGVPIEGIIFGGRRPAGVPLVYEALSWQHGVFVGAAMRSEATAAAEHKGKIIMHDPF
  AMRPFFGYNFGKYLAHWLSMAQHPAAKLPKIFHVNWFRKDKEGKFLWPGFGENSRVLEWM
  FNRIDGKASTKLTPIGYIPKEDALNLKGLGHINMMELFSISKEFWEKEVEDIEKYLEDQV
  NADLPCEIEREILALKQRISQM

• Sequence length: 622