PCK2

Summary

PCK2 (phosphoenolpyruvate carboxykinase 2, mitochondrial, HGNC:8725) is a protein-coding gene on chromosome 14q11.2-q12, encoding Phosphoenolpyruvate carboxykinase [GTP], mitochondrial (Q16822). Mitochondrial phosphoenolpyruvate carboxykinase that catalyzes the conversion of oxaloacetate (OAA) 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.

This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 5106 — RefSeq curated summary.

At a glance

• Gene–disease (curated): peripheral neuropathy (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 33 total
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_004563

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8725
Approved symbol	PCK2
Name	phosphoenolpyruvate carboxykinase 2, mitochondrial
Location	14q11.2-q12
Locus type	gene with protein product
Status	Approved
Aliases	PEPCK, PEPCK2
Ensembl gene	ENSG00000100889
Ensembl biotype	protein_coding
OMIM	614095
Entrez	5106

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 20 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216780, ENST00000396973, ENST00000545054, ENST00000557969, ENST00000558096, ENST00000558674, ENST00000559171, ENST00000559250, ENST00000559503, ENST00000559584, ENST00000559837, ENST00000560106, ENST00000560657, ENST00000560736, ENST00000561050, ENST00000561286, ENST00000905563, ENST00000905564, ENST00000905565, ENST00000905566, ENST00000905567, ENST00000905568, ENST00000905569, ENST00000905570, ENST00000905571, ENST00000934106, ENST00000958076

RefSeq mRNA: 4 — MANE Select: NM_004563 NM_001018073, NM_001291556, NM_001308054, NM_004563

CCDS: CCDS41928, CCDS76660, CCDS9609

Canonical transcript exons

ENST00000216780 — 10 exons

Exon	Start	End
ENSE00000654200	24102753	24102890
ENSE00002541482	24094311	24094434
ENSE00003489581	24099995	24100213
ENSE00003546979	24098203	24098387
ENSE00003554857	24096892	24097137
ENSE00003567725	24103160	24103255
ENSE00003595695	24099049	24099236
ENSE00003625222	24099558	24099720
ENSE00003640250	24098475	24098678
ENSE00003894179	24103510	24104125

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.6443 / max 918.2773, expressed in 1790 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138974	45.0347	1785
138973	0.5671	262
138975	0.0425	21

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.84	gold quality
mucosa of transverse colon	UBERON:0004991	96.78	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.89	gold quality
rectum	UBERON:0001052	94.01	gold quality
transverse colon	UBERON:0001157	93.02	gold quality
small intestine	UBERON:0002108	92.82	gold quality
mucosa of stomach	UBERON:0001199	92.67	gold quality
body of pancreas	UBERON:0001150	91.50	gold quality
granulocyte	CL:0000094	90.82	gold quality
right lobe of thyroid gland	UBERON:0001119	89.86	gold quality
left lobe of thyroid gland	UBERON:0001120	89.61	gold quality
liver	UBERON:0002107	89.10	gold quality
leukocyte	CL:0000738	88.59	gold quality
monocyte	CL:0000576	88.52	gold quality
vermiform appendix	UBERON:0001154	88.16	gold quality
spleen	UBERON:0002106	87.98	gold quality
pancreas	UBERON:0001264	87.97	gold quality
minor salivary gland	UBERON:0001830	87.79	gold quality
upper lobe of left lung	UBERON:0008952	87.67	gold quality
stromal cell of endometrium	CL:0002255	87.56	gold quality
metanephros cortex	UBERON:0010533	87.39	gold quality
omental fat pad	UBERON:0010414	87.37	gold quality
peritoneum	UBERON:0002358	87.24	gold quality
adult mammalian kidney	UBERON:0000082	87.23	gold quality
thyroid gland	UBERON:0002046	86.93	gold quality
duodenum	UBERON:0002114	86.79	gold quality
body of stomach	UBERON:0001161	86.50	gold quality
islet of Langerhans	UBERON:0000006	85.69	gold quality
left coronary artery	UBERON:0001626	85.39	gold quality
jejunal mucosa	UBERON:0000399	85.38	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, ATF3, ATF6, BHLHE40, CEBPA, CEBPB, CREB1, CREB3L3, CREBBP, ESRRA, FOS, FOXO1, FOXO4, HDAC3, HNF4A, JUN, KLF15, NCOA1, NCOR2, NFIA, NFIC, NR0B2, NR1H2, NR1H3, NR1H4, NR2F2, PPARGC1A, PROX1, RELA, SMAD6, SRCAP, USF1

miRNA regulators (miRDB)

24 targeting PCK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4724-3P	97.57	67.31	785
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-4693-5P	97.35	67.02	1234
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-571	95.38	66.54	671

Literature-anchored findings (GeneRIF, showing 33)

• Results suggest that pepck2 gene expression is regulated by its 5’ flanking region up to 822 bp, and 317 bp upstream of transcriptional start point. (PMID:15315819)
• Wild-type AREBP, but not Ser(470) to Ala(470) substituted non-phosphorylating mutant, represses gene expression of the phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme of gluconeogenesis. (PMID:17097062)
• skeletal muscle PEPCK has a role in determining physical activity levels (PMID:19521512)
• Increased transcriptional expression of PEPCK1 and G6Pc does not account for increased gluconeogenesis and fasting hyperglycemia in patients with type 2 diabetes mellitus. (PMID:19587243)
• Endoplasmic reticulum stress triggers suppression of AMPK while increasing C/EBPbeta and pCREB expression which activates PEPCK gene transcription. (PMID:20797423)
• results reveal a novel link between glucose metabolism and the DNA damage signaling pathway and suggest a possible role for PEPCK and G6P in the DNA damage response (PMID:21733854)
• expression of HCV nonstructural component NS5A in Huh7 or primary hepatocytes stimulated PEPCK gene expression and glucose output in HepG2 cells. (PMID:22955269)
• Expression of phosphoenolpyruvate carboxykinase linked to chemoradiation susceptibility of human colon cancer cells. (PMID:24602180)
• PEPCK activity was elevated threefold in lung cancer samples over normal lungs and its activation mediates an adaptive response to glucose depletion in lung cancer. (PMID:24632615)
• Amino acid limitation and ER stress inducers, conditions that activate the amino acid response (AAR) and the unfolded protein response (UPR), stimulate PCK2 gene transcription in tumor cell lines. (PMID:24973213)
• When autophagy was blocked, the level of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced in HepG2 cells and not in Hep3B cells. (PMID:26036577)
• Mitochondrial PCK2 regulates metabolic adaptation and enables glucose-independent tumor growth in various neoplasms. (PMID:26474064)
• Results indicate that PEPCK promotes tumor growth by increasing glucose and glutamine metabolism, increases anabolic metabolism and promotes mTORC1 activity. (PMID:26481663)
• ApoA-IV colocalizes with NR4A1, which suppresses G6Pase and PEPCK gene expression at the transcriptional level, reducing hepatic glucose output and lowering blood glucose. (PMID:26556724)
• Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma (PMID:28166201)
• Our study indicates that the T allele of the rs4982856 single-nucleotide polymorphisms in the PCK2 gene may be a risk factor for glucose intolerance after kidney transplantation (PMID:29731064)
• This study unveiled a novel role for PCK2 in integrating autophagy and bone formation, providing a potential target for stem cell-based bone tissue engineering that may lead to improved therapies for metabolic bone diseases. (PMID:31574189)
• The relationship between PEPCK metabolism in the urinary tract and insulin resistance and diabetes is reported. (PMID:32036699)
• Hypoxia increases the rate of renal gluconeogenesis via hypoxia-inducible factor-1-dependent activation of phosphoenolpyruvate carboxykinase expression. (PMID:32045650)
• Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress. (PMID:33052225)
• PURalpha Promotes the Transcriptional Activation of PCK2 in Oesophageal Squamous Cell Carcinoma Cells. (PMID:33142842)
• Proteomic Analysis of Hepatocellular Carcinoma Tissues With Encapsulation Shows Up-regulation of Leucine Aminopeptidase 3 and Phosphoenolpyruvate Carboxykinase 2. (PMID:33893083)
• Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis. (PMID:34020084)
• PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells. (PMID:34520823)
• A novel mutation in PCK2 gene causes primary angle-closure glaucoma. (PMID:34650006)
• Low expression of PCK2 in breast tumors contributes to better prognosis by inducing senescence of cancer cells. (PMID:35580079)
• Mitochondrial phosphoenolpyruvate carboxykinase promotes tumor growth in estrogen receptor-positive breast cancer via regulation of the mTOR pathway. (PMID:35757841)
• Role of PCK2 in the proliferation of vascular smooth muscle cells in neointimal hyperplasia. (PMID:35982907)
• Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells. (PMID:36002449)
• AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription. (PMID:37565737)
• Dysregulation of phosphoenolpyruvate carboxykinase in cancers: A comprehensive analysis. (PMID:38697449)
• Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma. (PMID:38890507)
• Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer. (PMID:39014441)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pck2	ENSDARG00000020956
mus_musculus	Pck2	ENSMUSG00000040618
rattus_norvegicus	Pck2	ENSRNOG00000018536
drosophila_melanogaster	Pepck1	FBGN0003067
drosophila_melanogaster	Pepck2	FBGN0034356
caenorhabditis_elegans	pck-2	WBGENE00011232
caenorhabditis_elegans		WBGENE00019151
caenorhabditis_elegans		WBGENE00021043

Paralogs (1): PCK1 (ENSG00000124253)

Protein

Protein identifiers

Phosphoenolpyruvate carboxykinase [GTP], mitochondrial — Q16822 (reviewed: Q16822)

Alternative names: Phosphoenolpyruvate carboxykinase 2, mitochondrial, Serine/threonine-protein kinase PCK2

All UniProt accessions (10): Q16822, A0A384MTT2, H0YKC4, H0YM31, H0YMA5, H0YML5, H0YMU6, H0YMY3, H0YNG4, H0YNH9

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial phosphoenolpyruvate carboxykinase that catalyzes the conversion of oxaloacetate (OAA) 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. Can play an active role in glyceroneogenesis and gluconeogenesis. Also acts as a serine/threonine-protein kinase: phosphorylates and activates ACSL4, thereby promoting ferroptosis.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Tissue specificity. Widely expressed.

Disease relevance. Mitochondrial phosphoenolpyruvate carboxykinase deficiency (M-PEPCKD) [MIM:261650] Metabolic disorder resulting from impaired gluconeogenesis. It is a rare disease with less than 10 cases reported in the literature. Clinical characteristics include hypotonia, hepatomegaly, failure to thrive, lactic acidosis and hypoglycemia. Autopsy reveals fatty infiltration of both the liver and kidneys. The disorder is transmitted as an autosomal recessive trait. The gene represented in this entry may be involved in disease pathogenesis.

Cofactor. Binds 1 Mn(2+) ion per subunit.

Pathway. Carbohydrate biosynthesis; gluconeogenesis.

Miscellaneous. In eukaryotes there are two isozymes: a cytoplasmic one and a mitochondrial one.

Similarity. Belongs to the phosphoenolpyruvate carboxykinase [GTP] family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q16822-1	1	yes
Q16822-2	2
Q16822-3	3

RefSeq proteins (4): NP_001018083, NP_001278485, NP_001294983, NP_004554* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008209	PEP_carboxykinase_GTP	Family
IPR008210	PEP_carboxykinase_N	Homologous_superfamily
IPR013035	PEP_carboxykinase_C	Homologous_superfamily
IPR018091	PEP_carboxykin_GTP_CS	Conserved_site
IPR035077	PEP_carboxykinase_GTP_C	Domain
IPR035078	PEP_carboxykinase_GTP_N	Domain

Pfam: PF00821, PF17297

Enzyme classification (BRENDA):

• EC 4.1.1.32 — phosphoenolpyruvate carboxykinase (GTP) (BRENDA: 33 organisms, 128 substrates, 87 inhibitors, 232 Km, 37 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GDP	0.003–20.6	44
CO2	0.0133–46	43
OXALOACETATE	0.004–2.5	41
PHOSPHOENOLPYRUVATE	0.0185–9.6	38
GTP	0.0074–1.6	25
IDP	0.013–2.5	15
ITP	0.05–40	11
2’-DEOXYGUANOSINE 5’-DIPHOSPHATE	0.053–0.19	3
2’-DEOXYGUANOSINE 5’-TRIPHOSPHATE	0.71–1.05	3
(Z)-3-FLUOROPHOSPHOENOLPYRUVATE	0.03	1
ADP	2.23	1
ATP	0.465	1

Catalyzed reactions (Rhea), 2 shown:

• oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 (RHEA:10388)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (41 total): binding site 20, sequence variant 7, modified residue 6, sequence conflict 4, splice variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16822-F1	94.04	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (20): 308; 309; 310; 329; 355; 421; 423; 454; 534; 543; 104; 548 …

Post-translational modifications (6): 42, 88, 115, 196, 304, 457

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70263	Gluconeogenesis

MSigDB gene sets: 389 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, WANG_CLIM2_TARGETS_UP, GRUETZMANN_PANCREATIC_CANCER_DN, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GNF2_HPN, GOBP_POLYOL_METABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KYNG_DNA_DAMAGE_DN, KYNG_DNA_DAMAGE_BY_4NQO

GO Biological Process (15): gluconeogenesis (GO:0006094), oxaloacetate metabolic process (GO:0006107), propionate catabolic process (GO:0019543), positive regulation of insulin secretion (GO:0032024), response to lipopolysaccharide (GO:0032496), cellular response to insulin stimulus (GO:0032869), response to starvation (GO:0042594), pyruvate biosynthetic process (GO:0042866), obsolete glycerol biosynthetic process from pyruvate (GO:0046327), hepatocyte differentiation (GO:0070365), cellular response to glucose stimulus (GO:0071333), cellular response to tumor necrosis factor (GO:0071356), cellular response to dexamethasone stimulus (GO:0071549), positive regulation of ferroptosis (GO:0160020), response to dexamethasone (GO:0071548)

GO Molecular Function (12): phosphoenolpyruvate carboxykinase activity (GO:0004611), phosphoenolpyruvate carboxykinase (GTP) activity (GO:0004613), protein serine/threonine kinase activity (GO:0004674), GTP binding (GO:0005525), manganese ion binding (GO:0030145), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), lyase activity (GO:0016829), carboxy-lyase activity (GO:0016831), purine nucleotide binding (GO:0017076), metal ion binding (GO:0046872)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glucose metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glucose metabolic process	1
hexose biosynthetic process	1
dicarboxylic acid metabolic process	1
propionate metabolic process	1
short-chain fatty acid catabolic process	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to stress	1
response to nutrient levels	1
pyruvate metabolic process	1
monocarboxylic acid biosynthetic process	1
liver development	1
epithelial cell differentiation	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1
cellular response to glucocorticoid stimulus	1
response to dexamethasone	1
cellular response to ketone	1
positive regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1
response to glucocorticoid	1
response to ketone	1
carboxy-lyase activity	1
phosphoenolpyruvate carboxykinase activity	1
protein kinase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

2070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCK2	G6PC1	P35575	924
PCK2	PC	P11498	864
PCK2	FBP1	P09467	794
PCK2	INS	P01308	790
PCK2	G6PC3	Q9BUM1	758
PCK2	G6PC2	Q9NQR9	758
PCK2	PPARGC1A	Q9UBK2	731
PCK2	PPARA	Q07869	726
PCK2	PPARG	P37231	690
PCK2	ACACA	Q13085	672
PCK2	ACOX1	Q15067	653
PCK2	SREBF1	P36956	642
PCK2	GCK	P35557	626
PCK2	UCP2	P55851	623
PCK2	FOXO1	Q12778	623

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
PCK2	IGHA1	psi-mi:“MI:0914”(association)	0.530
BBS2	PCK2	psi-mi:“MI:0914”(association)	0.510
PCK2	SMAD3	psi-mi:“MI:0915”(physical association)	0.510
APOD	PCK2	psi-mi:“MI:0915”(physical association)	0.400
EP300	PCK2	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
PCK2	PLPBP	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
SPHK1	MYO1C	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
COQ2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
P2RY6	RAVER1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
PCK2	PIGR	psi-mi:“MI:0914”(association)	0.350
MAIP1	TIMM44	psi-mi:“MI:0914”(association)	0.350
PRKCG	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
PRKCE	PAPSS1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
PA	ESYT2	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (159): HSPE1 (Co-fractionation), PPIA (Co-fractionation), UBE2L3 (Co-fractionation), PCK2 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), PRCC (Affinity Capture-MS), TSG101 (Affinity Capture-MS), PROSC (Affinity Capture-MS), CWC15 (Affinity Capture-MS), MUC13 (Affinity Capture-MS), PCK1 (Affinity Capture-MS), MUC5B (Affinity Capture-MS), BPIFB1 (Affinity Capture-MS), DMBT1 (Affinity Capture-MS), BPIFA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A4X1UM84, A0PMX1, A0QP32, A1KF31, A1U995, A3DJE3, A3PSV1, A4FQV7, A5TYT6, B2HMX9, B2JJT8, B2S270, B2U804, B4UDY7, B8J7G1, B8ZTI5, C1AJN6, O06084, O83159, O84716, P05153, P07379, P20007, P22130, P29190, P35558, P65687, P9WIH2, P9WIH3, Q05893, Q08262, Q16822, Q1BFN7, Q256B8, Q2IFT1, Q2L1L0, Q5L4X1, Q5P2P8, Q5R5J1, Q6F8P2

Diamond homologs: A0A4X1UM84, A0JSP6, A0PMX1, A0QP32, A1KF31, A1R317, A1T1K1, A1U995, A3DJE3, A3M840, A3PSV1, A4FQV7, A4QHQ4, A4T3S1, A4X388, A5TYT6, A8L175, A8M2V8, A9WL73, B0VDR1, B0VSN6, B2HMX9, B2HXC1, B2JJT8, B2S270, B2U804, B4UDY7, B7GY31, B7I624, B8J7G1, B8ZTI5, C0ZRP8, C1AJN6, C4LGT5, C6A0S4, O06084, O58050, O83159, O84716, P05153

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CEBPB	“up-regulates quantity by expression”	PCK2	“transcriptional regulation”
NR0B2	“down-regulates quantity by repression”	PCK2	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	PCK2	“transcriptional regulation”
NCOA1	“up-regulates quantity by expression”	PCK2	“transcriptional regulation”
RELA	“down-regulates quantity by repression”	PCK2	“transcriptional regulation”
PCK2	“down-regulates quantity”	oxaloacetate(2-)	“chemical modification”
PCK2	“up-regulates quantity”	phosphonatoenolpyruvate	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	5	18.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

33 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1621 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24097138:G:GC	donor_loss	1.0000
14:24097138:G:GG	donor_gain	1.0000
14:24097139:T:G	donor_loss	1.0000
14:24098676:AAGGT:A	donor_loss	1.0000
14:24098677:AGG:A	donor_loss	1.0000
14:24098678:GGT:G	donor_loss	1.0000
14:24098679:GT:G	donor_loss	1.0000
14:24098680:T:G	donor_loss	1.0000
14:24099167:G:GT	donor_gain	1.0000
14:24099549:A:AG	acceptor_gain	1.0000
14:24099549:AAT:A	acceptor_gain	1.0000
14:24099550:A:G	acceptor_gain	1.0000
14:24099551:T:TA	acceptor_gain	1.0000
14:24099553:CACA:C	acceptor_loss	1.0000
14:24099554:ACAG:A	acceptor_loss	1.0000
14:24099555:C:G	acceptor_gain	1.0000
14:24099555:CA:C	acceptor_loss	1.0000
14:24099556:A:AG	acceptor_gain	1.0000
14:24099557:G:A	acceptor_loss	1.0000
14:24099557:G:GG	acceptor_gain	1.0000
14:24099669:A:T	donor_gain	1.0000
14:24099672:GTGGA:G	donor_gain	1.0000
14:24099674:G:GT	donor_gain	1.0000
14:24099677:G:GG	donor_gain	1.0000
14:24100089:GA:G	donor_gain	1.0000
14:24100091:G:GG	donor_gain	1.0000
14:24102747:T:A	acceptor_gain	1.0000
14:24102748:GCCAG:G	acceptor_loss	1.0000
14:24102751:A:AG	acceptor_gain	1.0000
14:24102751:AG:A	acceptor_gain	1.0000

AlphaMissense

4175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24099691:A:C	D329A	1.000
14:24099691:A:T	D329V	1.000
14:24099625:G:A	G307D	0.999
14:24099690:G:C	D329H	0.999
14:24099691:A:G	D329G	0.999
14:24099692:T:A	D329E	0.999
14:24099692:T:G	D329E	0.999
14:24103548:T:C	F503L	0.999
14:24103550:T:A	F503L	0.999
14:24103550:T:G	F503L	0.999
14:24103640:C:A	N533K	0.999
14:24103640:C:G	N533K	0.999
14:24103641:T:A	W534R	0.999
14:24103641:T:C	W534R	0.999
14:24103644:T:C	F535L	0.999
14:24103646:C:A	F535L	0.999
14:24103646:C:G	F535L	0.999
14:24099152:C:A	N256K	0.998
14:24099152:C:G	N256K	0.998
14:24099167:G:C	K261N	0.998
14:24099167:G:T	K261N	0.998
14:24099228:C:G	H282D	0.998
14:24099615:A:C	S304R	0.998
14:24099617:T:A	S304R	0.998
14:24099617:T:G	S304R	0.998
14:24099625:G:T	G307V	0.998
14:24099627:A:C	K308Q	0.998
14:24099687:G:C	D328H	0.998
14:24099688:A:T	D328V	0.998
14:24099690:G:T	D329Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000635926 (14:24103842 G>A), RS1000849859 (14:24104355 T>C,G), RS1001063675 (14:24093569 C>A), RS1001094305 (14:24093288 G>C), RS1001338358 (14:24099810 A>C,G), RS1001649291 (14:24100014 C>G,T), RS1001660592 (14:24099639 G>A), RS1001764488 (14:24096014 A>T), RS1001795642 (14:24095701 A>C,G), RS1002105423 (14:24104484 A>G), RS1002504538 (14:24094913 C>A,T), RS1002595110 (14:24104212 TAGA>T), RS1002610939 (14:24104350 C>T), RS1002765949 (14:24097886 G>A,T), RS1002798897 (14:24097433 G>A,T)

Disease associations

OMIM: gene MIM:614095 | disease phenotypes: MIM:261650, MIM:613750

GenCC curated gene-disease

Disease	Classification	Inheritance
peripheral neuropathy	Moderate	Autosomal recessive
phosphoenolpyruvate carboxykinase deficiency	Supportive	Autosomal recessive
phosphoenolpyruvate carboxykinase deficiency, mitochondrial	Limited	Autosomal recessive

Mondo (4): phosphoenolpyruvate carboxykinase deficiency, mitochondrial (MONDO:0009864), retinitis pigmentosa 27 (MONDO:0013402), phosphoenolpyruvate carboxykinase deficiency (MONDO:0017320), peripheral neuropathy (MONDO:0005244)

Orphanet (3): Phosphoenolpyruvate carboxykinase deficiency (Orphanet:2880), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Phosphoenolpyruvate carboxykinase 2 deficiency (Orphanet:79317)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000799	Renal steatosis
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001325	Hypoglycemic coma
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001410	Decreased liver function
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0001988	Recurrent hypoglycemia
HP:0001998	Neonatal hypoglycemia
HP:0002013	Vomiting
HP:0002151	Increased circulating lactate concentration
HP:0002173	Hypoglycemic seizures
HP:0002329	Drowsiness
HP:0003128	Lactic acidosis
HP:0003217	Hyperglutaminemia
HP:0003648	Lacticaciduria
HP:0005959	Impaired gluconeogenesis
HP:0006846	Acute encephalopathy
HP:0012402	Increased urine alpha-ketoglutarate concentration
HP:0012758	Neurodevelopmental delay
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0034648	Elevated urine fumaric acid level

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010418_3	Liver fibrosis and steatohepatitis severity (MRI cT1 measure)	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006845	liver disease biomarker
EFO:0010821	liver fat measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C564890	Phosphoenolpyruvate Carboxykinase Deficiency, Mitochondrial (supp.)
C536654	Phosphoenolpyruvate carboxykinase deficiency (supp.)
C563526	Retinitis Pigmentosa 27 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3096 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.40	Kd	397.9	nM	CHEMBL3752910
6.40	ED50	397.9	nM	CHEMBL3752910
6.37	Kd	428.9	nM	CHEMBL5653589
6.37	ED50	428.9	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148946: Binding affinity to human PCK2 incubated for 45 mins by Kinobead based pull down assay	kd	0.3979	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148946: Binding affinity to human PCK2 incubated for 45 mins by Kinobead based pull down assay	kd	0.4289	uM

CTD chemical–gene interactions

134 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, affects expression, decreases expression	6
sodium arsenite	decreases expression, increases expression	5
Tetrachlorodibenzodioxin	decreases expression, increases expression, affects cotreatment	5
Cyclosporine	affects expression, increases expression	5
Aflatoxin B1	affects expression, decreases expression	4
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	4
bisphenol A	increases expression, affects expression, decreases expression	3
Cisplatin	affects expression, affects cotreatment, increases expression	3
Copper	affects binding, increases expression	3
mono-(2-ethylhexyl)phthalate	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
bisphenol AF	increases expression, decreases expression	2
Troglitazone	decreases expression, increases expression	2
Ethanol	increases abundance, increases expression, affects cotreatment, decreases expression	2
Atrazine	decreases expression, increases expression	2
Endosulfan	affects cotreatment, decreases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Fenofibrate	increases expression	2
Tunicamycin	decreases expression, increases expression	2
Thapsigargin	decreases expression, increases expression	2
Genistein	increases expression	2
GSK-J4	decreases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
moringin	affects cotreatment, decreases expression	1
perfluoropentanoic acid	increases expression	1
fluorotelomer sulfonic acids	increases expression	1
perfluorotridecanoic acid	increases expression	1
methyleugenol	decreases expression	1
benzo(b)fluoranthene	affects cotreatment, affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4415381	Binding	Binding affinity to PCKGM in human PC9 cells incubated for 1 hr by ABPP-SILAC assay	Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1GB	Abcam MCF-7 PCK2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.