PCK1

Summary

PCK1 (phosphoenolpyruvate carboxykinase 1, HGNC:8724) is a protein-coding gene on chromosome 20q13.31, encoding Phosphoenolpyruvate carboxykinase, cytosolic [GTP] (P35558). Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis.

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.

Source: NCBI Gene 5105 — RefSeq curated summary.

At a glance

• Gene–disease (curated): phosphoenolpyruvate carboxykinase deficiency, cytosolic (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 313 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_002591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8724
Approved symbol	PCK1
Name	phosphoenolpyruvate carboxykinase 1
Location	20q13.31
Locus type	gene with protein product
Status	Approved
Aliases	PEPCK-C
Ensembl gene	ENSG00000124253
Ensembl biotype	protein_coding
OMIM	614168
Entrez	5105

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 5 retained_intron

ENST00000319441, ENST00000467047, ENST00000470051, ENST00000475833, ENST00000485958, ENST00000498194, ENST00000851908, ENST00000851909, ENST00000851910, ENST00000851911, ENST00000851912, ENST00000851913, ENST00000965008

RefSeq mRNA: 1 — MANE Select: NM_002591 NM_002591

CCDS: CCDS13460

Canonical transcript exons

ENST00000319441 — 10 exons

Exon	Start	End
ENSE00000845754	57562071	57562252
ENSE00000845755	57562696	57562899
ENSE00000845757	57563565	57563727
ENSE00000845758	57564169	57564393
ENSE00001170096	57561110	57561203
ENSE00001259794	57565350	57568121
ENSE00003469184	57563028	57563215
ENSE00003533391	57561372	57561635
ENSE00003664134	57565040	57565135
ENSE00003669948	57564482	57564613

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 99.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 11.3823 / max 3120.4904, expressed in 163 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185479	11.3270	163
185480	0.0553	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.88	gold quality
adult organism	UBERON:0007023	99.50	gold quality
right lobe of liver	UBERON:0001114	99.48	gold quality
renal glomerulus	UBERON:0000074	99.15	gold quality
metanephric glomerulus	UBERON:0004736	99.11	gold quality
kidney epithelium	UBERON:0004819	99.04	gold quality
nephron tubule	UBERON:0001231	98.51	gold quality
adult mammalian kidney	UBERON:0000082	98.46	gold quality
colonic mucosa	UBERON:0000317	98.45	gold quality
renal medulla	UBERON:0000362	98.40	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.29	gold quality
liver	UBERON:0002107	98.25	gold quality
ileal mucosa	UBERON:0000331	97.82	gold quality
rectum	UBERON:0001052	97.25	gold quality
mucosa of transverse colon	UBERON:0004991	97.20	gold quality
duodenum	UBERON:0002114	96.06	gold quality
pericardium	UBERON:0002407	95.66	gold quality
kidney	UBERON:0002113	94.48	gold quality
synovial joint	UBERON:0002217	93.35	gold quality
adipose tissue	UBERON:0001013	92.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.27	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.19	gold quality
colonic epithelium	UBERON:0000397	90.98	gold quality
connective tissue	UBERON:0002384	90.97	gold quality
omental fat pad	UBERON:0010414	90.96	gold quality
peritoneum	UBERON:0002358	90.83	gold quality
cortex of kidney	UBERON:0001225	90.58	gold quality
transverse colon	UBERON:0001157	90.01	gold quality
small intestine	UBERON:0002108	89.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.14	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	76.53
E-MTAB-10553	yes	36.62
E-HCAD-10	yes	30.57
E-MTAB-8410	yes	16.57
E-CURD-135	no	2153.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF2, ATF3, ATF6, C1QTNF3, CEBPA, CEBPB, CEBPG, CREB1, CREB3L3, CREBBP, CREM, CRTC2, DBP, ELF1, ESR1, ESRRA, ESRRG, FOS, FOXA1, FOXA2, FOXC1, FOXM1, FOXO1, HIF1A, HNF1A, HNF4A, IRF6, JUN, NCOR2, NFIA, NFIC, NFKB, NR0B1, NR0B2, NR1D1, NR1H3, NR2C2, NR2F1, NR2F2

miRNA regulators (miRDB)

64 targeting PCK1, 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-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-498-5P	99.76	69.64	1807

Literature-anchored findings (GeneRIF, showing 40)

• crystal structure of human cytosolic phosphoenolpyruvate carboxykinase reveals a new GTP-binding site (PMID:11851336)
• Conserved amino acids within CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) regulate gene expression (PMID:11997389)
• promoter context may influence which domains within a transcription factor are employed to mediate transactivation of PEPCK (PMID:12237288)
• the PGC- 1-regulated phospho(enol)pyruvate carboxykinase (PEPCK) promoter is a novel target promoter for SHP inhibition (PMID:12324453)
• transcription of the gene for phosphoenolpyruvate carboxykinase (GTP) in the liver is regulated by SREBP-1c and Sp1 (PMID:14744869)
• Promoter single nucleotide polymorphism in PCK1 was resistant to down-regulation by insulin in vitro and associated with type 2 diabetes mellitus. (PMID:14764811)
• PCK1 has been implicated as one of many genes associated with type 2 diabetes mellitus [review] (PMID:15046742)
• AUF1 binds to multiple destabilizing elements within the 3’-UTR that participate in the rapid turnover of the phosphoenolpyruvate carboxykinase mRNA. (PMID:15951444)
• The multiple instability elements present within the 3’-UTR may function synergistically to mediate both the rapid degradation and the cAMP-induced stabilization of PEPCK mRNA. The latter process may result from a PKA-dependent phosphorylation of AUF1. (PMID:16144962)
• Subjects with the PCK1-232G/G genotype had more carotid IMT (0.80+/-0.02 versus 0.73+/-0.03 mm; P=0.007) but less TPV (0.10+/-0.09 versus 0.38+/-0.13; P=0.03) than subjects with other genotypes. (PMID:16282543)
• Significant association of single nucleotide polymorphism within three genes–PPARgamma, SOS2, and PCK1–with Alzheimer’s disease, was confirmed. (PMID:17440948)
• IFN-gamma exerts a tissue-specific action in rodents and humans, having glyceroneogenesis and the PEPCK-C gene as selective targets to intensify fatty acids release from adipocytes (PMID:17495004)
• The effects of several variants of retinoic acid on the expression and activity of PEPCK in human, mouse, and rat adipose tissue are reported. (PMID:18492826)
• Reduced CREB phosphorylation (Ser-129) associated with inactivation of GSK3beta by Ser-9 phosphorylation may be the major mechanism underlying PEPCK-C gene suppression by AMPK-activating agents such as biguanide (PMID:18801732)
• The aromatic ring of Tyr235 in PEPCK helps to position PEP in the active site and the hydroxyl group allows an optimal PEP-Mn(2+) distance for efficient phosphoryl transfer and overall catalysis. (PMID:19021757)
• Val184 of PCK1 gene might increase the risk of type 2 diabetes in eastern Chinese population with BMI<23 kg/m(2) via reducing the PEPCK-C activity. (PMID:19070910)
• Study validated a predicted SP1 binding site in the control of PCK1 transcription using gel shift and reporter assays. (PMID:19329064)
• study is the first to investigate the association between variants of the PCK1 gene and type 2 diabetes in South Asians (PMID:19725958)
• Study in the EYHS cohort failed to identify an association of PCK1 polymorphisms with obesity, physical activity, and fitness. (PMID:20134411)
• Data show PEPCK-C and CPT-1 mRNAs are more abundant in non-tumoral tissues than in the tumoral counterpart, whereas the opposite occurred for the FAS gene. (PMID:20691246)
• Studies demonstrate the association between PCK1 and smaller average brain volume. (PMID:21152065)
• Acetylation regulates the stability of the gluconeogenic rate-limiting enzyme PEPCK1. (PMID:21726808)
• HCV core protein expression-mediated FOXO1 activation and the increased PGC-1alpha leaded to the elevation of PCK1 at the mRNA level (PMID:22489460)
• The PCK1 tag-single nucleotide polymorphisms influenced insulin resistance by interacting with plasma n-3 polyunsaturated fatty acids levels in metabolic syndrome patients. (PMID:23092637)
• Lipopolysaccharide and monophosphoryl lipid A also up-regulated G6PC and PCK1 transcript abundance in a TLR4-dependent manner. (PMID:23465595)
• A mutation of PCK1 associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. (PMID:24863970)
• Insulin-dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N-methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region (PMID:25736587)
• an extended binding site in the catalytic cleft of cPEPCK which is used by 3-MPA to inhibit cPEPCK non-competitively. (PMID:26528723)
• HBXIP is able to depress the gluconeogenesis in hepatoma cells by suppressing PCK1 to promote hepatocarcinogenesis, involving miR-135a/FOXO1 axis and PI3K/Akt/p-FOXO1 pathway. (PMID:27609066)
• Study identified a novel homozygous PCK1 missense mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia. (PMID:28216384)
• This study reveals a unique mechanism to suppress hepatocellular carcinoma by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation. (PMID:28240261)
• Study investigated the molecular basis of such effects focusing on a commonly studied polymorphism in pig Pgc1alpha, which changes a cysteine at position 430 (WT) of the protein to a serine (C430S); found that differential O-GlcNAcylation of Pgc1alpha regulates PCK1 activity and this molecular mechanism could explain at least in part the epistatic interaction between both genes. (PMID:28644880)
• PCK1 is detrimental to malignant hepatocytes and activating PCK1 expression is a potential treatment strategy for patients with hepatocellular carcinoma. (PMID:29335519)
• circC3P1 acts as a tumor suppressor via enhancing PCK1 expression by sponging miR-4641 in hepatocellular carcinoma. (PMID:29608893)
• The expression levels of PCK1 were suppressed in hepatocellular carcinoma (HCC) samples and in cells derived from HCC tissues. (PMID:29768256)
• These data suggested that PCK1 induced by Hepatitis B virus X protein led to decreased Hepatitis B virus replication through the downregulation of PGC-1alpha and PPAR-gamma. (PMID:30168585)
• This study revealed that PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the AMPK/p27(Kip1) axis and supports a potential therapeutic and protective effect of metformin on hepatocellular carcinoma. (PMID:30717766)
• SLC2A4, RBP4, PCK1, and PIK3R1 genes may be involved in the pathogenesis of GDM. (PMID:30805369)
• Cytosolic phosphoenolpyruvate carboxykinase is expressed in alpha-cells from human and murine pancreas. (PMID:31180589)
• Results find that PCK1 level was upregulated in biliary atresia patients who had successful Kasai portoenterostomy (KPE), while there was a significant down regulation in patients who failed KPE. These data suggest that down regulation of PCK1 is a biological marker for good prognosis of patients with biliary atresia. (PMID:31342296)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	pck1	ENSDARG00000013522
mus_musculus	Pck1	ENSMUSG00000027513
rattus_norvegicus	Pck1	ENSRNOG00000028616
drosophila_melanogaster	Pepck1	FBGN0003067
drosophila_melanogaster	Pepck2	FBGN0034356
caenorhabditis_elegans	pck-2	WBGENE00011232
caenorhabditis_elegans		WBGENE00019151
caenorhabditis_elegans		WBGENE00021043

Paralogs (1): PCK2 (ENSG00000100889)

Protein

Protein identifiers

Phosphoenolpyruvate carboxykinase, cytosolic [GTP] — P35558 (reviewed: P35558)

Alternative names: Serine-protein kinase PCK1

All UniProt accessions (1): P35558

UniProt curated annotations — full annotation on UniProt →

Function. Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis. Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle. 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. At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate. Acts as a regulator of formation and maintenance of memory CD8(+) T-cells: up-regulated in these cells, where it generates phosphoenolpyruvate, via gluconeogenesis. The resultant phosphoenolpyruvate flows to glycogen and pentose phosphate pathway, which is essential for memory CD8(+) T-cells homeostasis. 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. 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.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum.

Tissue specificity. Major sites of expression are liver, kidney and adipocytes.

Post-translational modifications. Acetylated. Lysine acetylation by p300/EP300 is increased on high glucose conditions. Lysine acetylation promotes ubiquitination by UBR5. 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. Phosphorylated in a GSK3B-mediated pathway; phosphorylation affects the efficiency of SIRT1-mediated deacetylation, and regulates PCK1 ubiquitination and degradation. 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. Ubiquitination by UBR5 leads to proteasomal degradation.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Phosphoenolpyruvate carboxykinase activity is regulated by acetylation and glucose levels. The anaplerotic conversion of phosphoenolpyruvate to oxaloacetate is improved by PCK1 acetylation on Lys-91 (K91ac), Lys-473 (K473ac) and Lys-521 (K521ac). 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. Phosphorylation at Ser-90 reduces the binding affinity to oxaloacetate and converts the enzyme into an atypical protein kinase using GTP as donor.

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

Induction. Regulated by cAMP and insulin.

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 (2)

UniProt ID	Names	Canonical?
P35558-1	1	yes
P35558-2	2

RefSeq proteins (1): NP_002582* (*=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-seryl-[protein] + GTP = O-phospho-L-seryl-[protein] + GDP + H(+) (RHEA:64020)

UniProt features (118 total): strand 35, helix 27, modified residue 12, sequence variant 12, binding site 11, mutagenesis site 6, turn 5, sequence conflict 5, splice variant 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1KHB	X-RAY DIFFRACTION	1.85
1KHF	X-RAY DIFFRACTION	2.02
1NHX	X-RAY DIFFRACTION	2.1
1M51	X-RAY DIFFRACTION	2.25
2GMV	X-RAY DIFFRACTION	2.3
1KHG	X-RAY DIFFRACTION	2.34
1KHE	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35558-F1	96.60	0.94

Functional residue map

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

Catalytic / active sites (1): 288

Ligand- & substrate-binding residues (11): 403–405; 405; 436; 530–533; 87; 235–237; 244; 264; 286; 287–292; 311

Post-translational modifications (12): 19, 70, 71, 90, 91, 118, 178, 286, 473, 521, 524, 594

Mutagenesis-validated functional residues (6):

Position	Phenotype
70	abolishes acetylation and increases protein stability; when associated with r-71 and r-594.
71	abolishes acetylation and increases protein stability; when associated with r-70 and r-594.
90	abolished phosphorylation by akt1, interaction with insig proteins (insig1 and insig2) and ability to regulate lipogenes
90	phosphomimetic mutant, promotes the serine protein kinase activity by reducing the binding affinity to oxaloacetate.
288	abolished both phosphoenolpyruvate carboxykinase and protein kinase activities.
594	abolishes acetylation and increases protein stability; when associated with r-70 and r-71.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2161541	Abacavir metabolism
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-70263	Gluconeogenesis
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9632974	NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis
R-HSA-9940951	Interaction of NuRD complexes with transcription factors

MSigDB gene sets: 419 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, PID_HNF3B_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GNF2_GSTM1, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_CORTICOSTEROID, GNF2_HPN, GOBP_PEPTIDYL_SERINE_MODIFICATION

GO Biological Process (28): glucose metabolic process (GO:0006006), gluconeogenesis (GO:0006094), oxaloacetate metabolic process (GO:0006107), response to bacterium (GO:0009617), response to acidic pH (GO:0010447), peptidyl-serine phosphorylation (GO:0018105), propionate catabolic process (GO:0019543), response to insulin (GO:0032868), cellular response to insulin stimulus (GO:0032869), glucose homeostasis (GO:0042593), response to starvation (GO:0042594), positive regulation of memory T cell differentiation (GO:0043382), positive regulation of transcription by RNA polymerase II (GO:0045944), glyceraldehyde-3-phosphate biosynthetic process (GO:0046166), obsolete glycerol biosynthetic process from pyruvate (GO:0046327), positive regulation of lipid biosynthetic process (GO:0046889), regulation of lipid biosynthetic process (GO:0046890), cellular response to potassium ion starvation (GO:0051365), hepatocyte differentiation (GO:0070365), cellular response to glucose stimulus (GO:0071333), cellular response to dexamethasone stimulus (GO:0071549), tricarboxylic acid metabolic process (GO:0072350), NLS-bearing protein import into nucleus (GO:0006607), lipid metabolic process (GO:0006629), SREBP-SCAP complex retention in endoplasmic reticulum (GO:0036316), dicarboxylic acid metabolic process (GO:0043648), positive regulation of cholesterol biosynthetic process (GO:0045542), protein maturation (GO:0051604)

GO Molecular Function (14): magnesium ion binding (GO:0000287), phosphoenolpyruvate carboxykinase (GTP) activity (GO:0004613), GTP binding (GO:0005525), manganese ion binding (GO:0030145), carboxylic acid binding (GO:0031406), protein serine kinase activity (using GTP as donor) (GO:0106264), nucleotide binding (GO:0000166), phosphoenolpyruvate carboxykinase activity (GO:0004611), kinase activity (GO:0016301), transferase activity (GO:0016740), lyase activity (GO:0016829), carboxy-lyase activity (GO:0016831), purine nucleotide binding (GO:0017076), metal ion binding (GO:0046872)

GO Cellular Component (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Abacavir ADME	1
Adipogenesis	1
Glucose metabolism	1
FOXO-mediated transcription	1
NR1H2 and NR1H3-mediated signaling	1
NuRD complex assembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
lipid biosynthetic process	2
catalytic activity	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
hexose metabolic process	1
glucose metabolic process	1
hexose biosynthetic process	1
dicarboxylic acid metabolic process	1
response to other organism	1
response to pH	1
protein phosphorylation	1
peptidyl-serine modification	1
propionate metabolic process	1
short-chain fatty acid catabolic process	1
response to peptide hormone	1
response to insulin	1
cellular response to peptide hormone stimulus	1
carbohydrate homeostasis	1
response to stress	1
response to nutrient levels	1
positive regulation of immune effector process	1
memory T cell differentiation	1
regulation of memory T cell differentiation	1
positive regulation of T cell differentiation	1
positive regulation of immune response	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
glyceraldehyde-3-phosphate metabolic process	1
aldehyde biosynthetic process	1
organophosphate biosynthetic process	1
carbohydrate derivative biosynthetic process	1
positive regulation of biosynthetic process	1
positive regulation of lipid metabolic process	1
regulation of lipid biosynthetic process	1
regulation of biosynthetic process	1
regulation of lipid metabolic process	1
cellular response to starvation	1
liver development	1

Protein interactions and networks

STRING

2564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCK1	G6PC1	P35575	926
PCK1	FBP1	P09467	805
PCK1	G6PC3	Q9BUM1	804
PCK1	G6PC2	Q9NQR9	802
PCK1	PPARG	P37231	801
PCK1	UBR5	O95071	774
PCK1	PC	P11498	770
PCK1	SCD	O00767	738
PCK1	GCK	P35557	723
PCK1	GPAM	Q9HCL2	701
PCK1	PFKFB1	P16118	690
PCK1	FASN	P49327	687
PCK1	INS	P01308	684
PCK1	PKLR	P11973	676
PCK1	SCD5	Q86SK9	675

IntAct

39 interactions, top by confidence:

A	B	Type	Score
SCAMP1	DNAJC13	psi-mi:“MI:0914”(association)	0.620
PCK2	IGHA1	psi-mi:“MI:0914”(association)	0.530
ANGPTL7	TCP1	psi-mi:“MI:0914”(association)	0.530
ZMYM2	HDAC3	psi-mi:“MI:0914”(association)	0.480
ZNF585B	PCK1	psi-mi:“MI:0915”(physical association)	0.400
SOCS2	PCK1	psi-mi:“MI:0915”(physical association)	0.400
ZMYM5	PCK1	psi-mi:“MI:0915”(physical association)	0.400
PCK1	C1R	psi-mi:“MI:0915”(physical association)	0.370
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
PCK2	PIGR	psi-mi:“MI:0914”(association)	0.350
ATP6V0A4	ATP6V0C	psi-mi:“MI:0914”(association)	0.350
TRIM8	PCK1	psi-mi:“MI:0914”(association)	0.350
CLUAP1	UBA6	psi-mi:“MI:0914”(association)	0.350
ATPSCKMT	POTEF	psi-mi:“MI:0914”(association)	0.350
NHLRC1	TK2	psi-mi:“MI:0914”(association)	0.350
PRDX2	TXNDC9	psi-mi:“MI:0914”(association)	0.350
MRPS18B	GAPDHS	psi-mi:“MI:0914”(association)	0.350
TMLHE	GAPDHS	psi-mi:“MI:0914”(association)	0.350
SNX21	ACOT8	psi-mi:“MI:0914”(association)	0.350
CST5	HS3ST1	psi-mi:“MI:0914”(association)	0.350
SMPD2	GPAA1	psi-mi:“MI:0914”(association)	0.350
TGFA	ORC4	psi-mi:“MI:0914”(association)	0.350
CRCP	PRPF40A	psi-mi:“MI:0914”(association)	0.350
CNP	UBB	psi-mi:“MI:0914”(association)	0.350
DNAJC3	PYGM	psi-mi:“MI:0914”(association)	0.350
MYEOV	PYGM	psi-mi:“MI:0914”(association)	0.350
CIB3	PCK1	psi-mi:“MI:0914”(association)	0.350
MXD3	PCK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (137): PCK1 (Affinity Capture-MS), PCK1 (Affinity Capture-MS), PCK1 (Affinity Capture-Western), UBE2I (Affinity Capture-Western), PCK1 (Affinity Capture-Western), PCK1 (Affinity Capture-Western), UBR5 (Reconstituted Complex), PCK1 (Reconstituted Complex), PCK1 (Affinity Capture-MS), PCK1 (Affinity Capture-MS), INSIG1 (Affinity Capture-Western), INSIG2 (Affinity Capture-Western), INSIG1 (Co-fractionation), PCK1 (Reconstituted Complex), PCK1 (Biochemical Activity)

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

20 interactions.

A	Effect	B	Mechanism
HNF4A	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”
ZNF692	“down-regulates quantity by repression”	PCK1	“transcriptional regulation”
metformin	“down-regulates quantity”	PCK1
FOXO1	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”
FOXO	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”
CRTC2	“up-regulates quantity”	PCK1	“transcriptional regulation”
NR3C1	“up-regulates quantity”	PCK1	“transcriptional regulation”
PCK1	“up-regulates quantity”	phosphonatoenolpyruvate	“chemical modification”
PCK1	“down-regulates quantity”	oxaloacetate(2-)	“chemical modification”
EP300	“down-regulates quantity by destabilization”	PCK1	acetylation
BAG6	“down-regulates quantity by destabilization”	PCK1	acetylation
SIRT2	“up-regulates quantity by stabilization”	PCK1	deacetylation
UBR5	“down-regulates quantity by destabilization”	PCK1	ubiquitination
ZBTB46	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	164
Likely benign	73
Benign	31

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2227997	NM_002591.4(PCK1):c.1234C>T (p.Gln412Ter)	Pathogenic
2502278	NM_002591.4(PCK1):c.574T>C (p.Cys192Arg)	Pathogenic
440852	PCK1, 12-BP DEL, NT369	Pathogenic
3767977	NM_002591.4(PCK1):c.705C>G (p.Tyr235Ter)	Likely pathogenic
3911871	NM_002591.4(PCK1):c.1833_1834del (p.Glu611fs)	Likely pathogenic
4849447	NM_002591.4(PCK1):c.1299dup (p.Gly434fs)	Likely pathogenic
931905	NM_002591.4(PCK1):c.961+1G>A	Likely pathogenic

SpliceAI

1002 predictions. Top by Δscore:

Variant	Effect	Δscore
20:57561199:GAAAG:G	donor_gain	1.0000
20:57561200:AAAG:A	donor_gain	1.0000
20:57561201:AAG:A	donor_gain	1.0000
20:57561202:AG:A	donor_gain	1.0000
20:57561203:GG:G	donor_gain	1.0000
20:57561203:GGTA:G	donor_loss	1.0000
20:57561204:G:GG	donor_gain	1.0000
20:57561204:GT:G	donor_loss	1.0000
20:57561621:G:GT	donor_gain	1.0000
20:57561635:GGTAA:G	donor_loss	1.0000
20:57561636:G:GG	donor_gain	1.0000
20:57561636:GTAAG:G	donor_loss	1.0000
20:57561637:T:A	donor_loss	1.0000
20:57562069:AGCT:A	acceptor_gain	1.0000
20:57562070:GCTG:G	acceptor_gain	1.0000
20:57562693:TAGG:T	acceptor_loss	1.0000
20:57562694:A:C	acceptor_loss	1.0000
20:57562695:G:GA	acceptor_loss	1.0000
20:57562833:G:GT	donor_gain	1.0000
20:57562850:G:GT	donor_gain	1.0000
20:57562850:G:T	donor_gain	1.0000
20:57562896:CAAA:C	donor_gain	1.0000
20:57562896:CAAAG:C	donor_loss	1.0000
20:57562898:AA:A	donor_gain	1.0000
20:57562898:AAGT:A	donor_loss	1.0000
20:57562899:AGT:A	donor_loss	1.0000
20:57562900:G:GG	donor_gain	1.0000
20:57562900:GT:G	donor_loss	1.0000
20:57562901:TAAGT:T	donor_loss	1.0000
20:57563189:G:GT	donor_gain	1.0000

AlphaMissense

4139 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:57563698:A:C	D311A	1.000
20:57563698:A:T	D311V	1.000
20:57563631:G:T	G289W	0.999
20:57563632:G:A	G289E	0.999
20:57563642:C:A	N292K	0.999
20:57563642:C:G	N292K	0.999
20:57563694:G:C	D310H	0.999
20:57563695:A:T	D310V	0.999
20:57563697:G:C	D311H	0.999
20:57563699:C:A	D311E	0.999
20:57563699:C:G	D311E	0.999
20:57565480:C:A	N515K	0.999
20:57565480:C:G	N515K	0.999
20:57565481:T:A	W516R	0.999
20:57565481:T:C	W516R	0.999
20:57565514:T:A	W527R	0.999
20:57565514:T:C	W527R	0.999
20:57563611:C:A	A282D	0.998
20:57563622:A:C	S286R	0.998
20:57563624:C:A	S286R	0.998
20:57563624:C:G	S286R	0.998
20:57563632:G:T	G289V	0.998
20:57563634:A:C	K290Q	0.998
20:57563644:T:C	L293P	0.998
20:57563647:C:A	A294D	0.998
20:57563691:G:T	G309W	0.998
20:57563692:G:A	G309E	0.998
20:57563695:A:C	D310A	0.998
20:57563698:A:G	D311G	0.998
20:57563706:T:A	W314R	0.998

dbSNP variants (sampled 300 via entrez): RS1000383243 (20:57559361 C>G), RS1001026344 (20:57568506 T>C,G), RS1001331527 (20:57560201 C>A), RS1001851819 (20:57563875 G>A), RS1001887651 (20:57566050 T>A,G), RS1001912906 (20:57565135 G>A), RS1001955459 (20:57565015 T>C), RS1003725181 (20:57561885 T>C), RS1004069299 (20:57563527 G>A), RS1004476039 (20:57566563 C>A,T), RS1004557439 (20:57559720 A>T), RS1004616267 (20:57560184 G>A), RS1004704491 (20:57561529 C>A,T), RS1004794764 (20:57565083 C>T), RS1004909350 (20:57564832 G>A)

Disease associations

OMIM: gene MIM:614168 | disease phenotypes: MIM:261680, MIM:120435

GenCC curated gene-disease

Disease	Classification	Inheritance
phosphoenolpyruvate carboxykinase deficiency, cytosolic	Strong	Autosomal recessive
phosphoenolpyruvate carboxykinase deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
phosphoenolpyruvate carboxykinase deficiency, cytosolic	Definitive	AR

Mondo (3): phosphoenolpyruvate carboxykinase deficiency, cytosolic (MONDO:0009866), Lynch syndrome 1 (MONDO:0007356), phosphoenolpyruvate carboxykinase deficiency (MONDO:0017320)

Orphanet (3): Phosphoenolpyruvate carboxykinase deficiency (Orphanet:2880), Lynch syndrome (Orphanet:144), OBSOLETE: Phosphoenolpyruvate carboxykinase 1 deficiency (Orphanet:79316)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000648	Optic atrophy
HP:0000799	Renal steatosis
HP:0000961	Cyanosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
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:0002059	Cerebral atrophy
HP:0002104	Apnea
HP:0002151	Increased circulating lactate concentration
HP:0002173	Hypoglycemic seizures
HP:0002240	Hepatomegaly
HP:0002329	Drowsiness
HP:0002353	EEG abnormality
HP:0002480	Hepatic encephalopathy
HP:0002919	Ketonuria
HP:0003128	Lactic acidosis
HP:0003162	Fasting hypoglycemia
HP:0003217	Hyperglutaminemia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001738_1	Response to fenofibrate (adiponectin levels)	2.000000e-07
GCST001809_13	Type 2 diabetes	2.000000e-06
GCST002945_31	Emphysema imaging phenotypes	5.000000e-07
GCST002945_6	Emphysema imaging phenotypes	9.000000e-07
GCST004639_8	Prudent dietary pattern	2.000000e-06
GCST006613_64	Triglycerides	4.000000e-08
GCST008058_88	Estimated glomerular filtration rate	6.000000e-21
GCST008059_89	Estimated glomerular filtration rate	1.000000e-19
GCST008747_32	Estimated glomerular filtration rate	4.000000e-13
GCST009652_33	Serum alkaline phosphatase levels	3.000000e-08
GCST90002383_305	Hematocrit	2.000000e-20
GCST90002384_476	Hemoglobin	1.000000e-24
GCST90002403_528	Red blood cell count	2.000000e-17

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0008111	diet measurement
EFO:0004530	triglyceride measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C536654	Phosphoenolpyruvate carboxykinase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2911 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4810083	PCK1		0.00	0

ChEMBL bioactivities

21 potent at pChembl≥5 of 21 total, top 21 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.64	IC50	230	nM	CHEMBL243342
6.62	IC50	240	nM	CHEMBL394621
6.54	IC50	290	nM	CHEMBL389494
6.47	IC50	340	nM	CHEMBL243343
6.41	IC50	390	nM	CHEMBL243134
6.35	IC50	450	nM	CHEMBL243180
6.27	IC50	540	nM	CHEMBL243116
6.20	IC50	630	nM	CHEMBL245018
6.16	IC50	690	nM	CHEMBL244165
6.10	IC50	790	nM	CHEMBL394368
6.02	IC50	960	nM	CHEMBL244802
5.90	IC50	1250	nM	CHEMBL244590
5.81	IC50	1560	nM	CHEMBL389111
5.75	IC50	1800	nM	CHEMBL397513
5.71	IC50	1950	nM	CHEMBL242486
5.68	IC50	2070	nM	CHEMBL244589
5.68	IC50	2110	nM	CHEMBL120708
5.64	IC50	2300	nM	CHEMBL428567
5.59	IC50	2560	nM	CHEMBL242862
5.25	IC50	5650	nM	CHEMBL396498
5.06	IC50	8700	nM	CHEMBL242437

PubChem BioAssay actives

21 with measured affinity, of 25 total; 21 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
2-amino-N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-4-methyl-1,3-thiazole-5-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.2300	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-1,3-dimethylpyrazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.2400	uM
5-chloro-N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-1,3-dimethylpyrazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.2900	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-1,2-dimethylimidazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.3400	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-1-methylpyrazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.3900	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]quinoline-8-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.4500	uM
N-[4-[[3-butyl-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-5-chloro-1,3-dimethylpyrazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.5400	uM
N-[4-[[3-butyl-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-1-methylimidazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.6300	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]acetamide	290930: Inhibition of human cPEPCK	ic50	0.6900	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide	290930: Inhibition of human cPEPCK	ic50	0.7900	uM
3-(cyclopropylmethyl)-8-[[4-(dimethylsulfamoylamino)phenyl]methyl]-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purine	290930: Inhibition of human cPEPCK	ic50	0.9600	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]methanesulfonamide	290930: Inhibition of human cPEPCK	ic50	1.2500	uM
8-[(4-aminophenyl)methyl]-3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-7H-purine-2,6-dione	290930: Inhibition of human cPEPCK	ic50	1.5600	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-2,2,2-trifluoroacetamide	290930: Inhibition of human cPEPCK	ic50	1.8000	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]pyridine-3-sulfonamide	290930: Inhibition of human cPEPCK	ic50	1.9500	uM
N-[4-[[3-(cyclopropylmethyl)-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-2-(dimethylamino)acetamide	290930: Inhibition of human cPEPCK	ic50	2.0700	uM
N-[4-[[3-butyl-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]acetamide	290930: Inhibition of human cPEPCK	ic50	2.1100	uM
N-[4-[[3-butyl-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]-2,2,2-trifluoroacetamide	290930: Inhibition of human cPEPCK	ic50	2.3000	uM
8-[(4-aminophenyl)methyl]-3-butyl-1-[(2-fluorophenyl)methyl]-7H-purine-2,6-dione	290930: Inhibition of human cPEPCK	ic50	2.5600	uM
3-butyl-8-[(2,4-diaminophenyl)methyl]-1-[(2-fluorophenyl)methyl]-7H-purine-2,6-dione	290930: Inhibition of human cPEPCK	ic50	5.6500	uM
N-[3-acetamido-4-[[3-butyl-1-[(2-fluorophenyl)methyl]-2,6-dioxo-7H-purin-8-yl]methyl]phenyl]acetamide	290930: Inhibition of human cPEPCK	ic50	8.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression, increases expression, increases methylation (+1 more)	6
Tetrachlorodibenzodioxin	decreases expression, increases expression, affects expression	5
sodium arsenite	decreases expression, increases expression	4
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, increases expression, affects binding, decreases reaction, decreases expression (+1 more)	4
Dexamethasone	decreases expression, decreases reaction, increases reaction, increases expression, affects cotreatment	4
perfluorooctanoic acid	increases expression	3
bisphenol S	decreases expression, increases expression	3
Acetaminophen	decreases expression	3
Valproic Acid	decreases methylation, affects reaction, increases expression	3
dorsomorphin	affects cotreatment, increases expression, decreases expression, decreases reaction	2
bisphenol AF	decreases expression, increases expression	2
Leflunomide	decreases reaction, increases expression	2
Cadmium	decreases reaction, increases abundance, increases expression, decreases expression	2
Endosulfan	decreases expression, increases expression	2
Estradiol	affects binding, decreases reaction, decreases expression, affects cotreatment, increases reaction	2
Rifampin	affects cotreatment, increases expression, decreases reaction	2
Silicon Dioxide	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases expression, affects expression, decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases expression, decreases expression	2
bisphenol F	increases expression	1
betulin	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	increases expression	1
fenofibric acid	increases expression, affects binding	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
trichostatin A	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
aluminum chlorhydrate	decreases expression, increases abundance	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
CHEMBL889299	Binding	Inhibition of human cPEPCK	C-8 Modifications of 3-alkyl-1,8-dibenzylxanthines as inhibitors of human cytosolic phosphoenolpyruvate carboxykinase. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1Y5	Abcam A-549 PCK1 KO	Cancer cell line	Male
CVCL_D2CD	Abcam HCT 116 PCK1 KO	Cancer cell line	Male
CVCL_E0US	Ubigene Hep G2 PCK1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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