Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNWEJ5Y)

• DOT Name: Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)
• Synonyms: PEPCK-C; EC 4.1.1.32; Serine-protein kinase PCK1; EC 2.7.11.-
• Gene Name: PCK1
• Related Disease:
  Phosphoenolpyruvate carboxykinase deficiency, cytosolic
  Phosphoenolpyruvate carboxykinase deficiency
• UniProt ID: PCKGC_HUMAN
• PDB ID: 1KHB; 1KHE; 1KHF; 1KHG; 1M51; 1NHX; 2GMV
• EC Number: 2.7.11.-; 4.1.1.32
• Pfam ID: PF00821 ; PF17297
• Sequence:
  MPPQLQNGLNLSAKVVQGSLDSLPQAVREFLENNAELCQPDHIHICDGSEEENGRLLGQM
  EEEGILRRLKKYDNCWLALTDPRDVARIESKTVIVTQEQRDTVPIPKTGLSQLGRWMSEE
  DFEKAFNARFPGCMKGRTMYVIPFSMGPLGSPLSKIGIELTDSPYVVASMRIMTRMGTPV
  LEAVGDGEFVKCLHSVGCPLPLQKPLVNNWPCNPELTLIAHLPDRREIISFGSGYGGNSL
  LGKKCFALRMASRLAKEEGWLAEHMLILGITNPEGEKKYLAAAFPSACGKTNLAMMNPSL
  PGWKVECVGDDIAWMKFDAQGHLRAINPENGFFGVAPGTSVKTNPNAIKTIQKNTIFTNV
  AETSDGGVYWEGIDEPLASGVTITSWKNKEWSSEDGEPCAHPNSRFCTPASQCPIIDAAW
  ESPEGVPIEGIIFGGRRPAGVPLVYEALSWQHGVFVGAAMRSEATAAAEHKGKIIMHDPF
  AMRPFFGYNFGKYLAHWLSMAQHPAAKLPKIFHVNWFRKDKEGKFLWPGFGENSRVLEWM
  FNRIDGKASTKLTPIGYIPKEDALNLKGLGHINMMELFSISKEFWEKEVEDIEKYLEDQV
  NADLPCEIEREILALKQRISQM
• 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.
• Tissue Specificity: Major sites of expression are liver, kidney and adipocytes.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Citrate cycle (TCA cycle) (hsa00020)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
  FoxO sig.ling pathway (hsa04068)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Insulin sig.ling pathway (hsa04910)
  Adipocytokine sig.ling pathway (hsa04920)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Gluconeogenesis (R-HSA-70263)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis (R-HSA-9632974)
  Abacavir metabolism (R-HSA-2161541)
• BioCyc Pathway: MetaCyc:HS04751-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Phosphoenolpyruvate carboxykinase deficiency, cytosolic	DIS2LXNC	Strong	Autosomal recessive	[1]
Phosphoenolpyruvate carboxykinase deficiency	DISOMDLN	Supportive	Autosomal recessive	[2]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[29]

45 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[15]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[20]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[21]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[22]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[23]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[24]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[25]
Clopidogrel	DMOL54H	Approved	Clopidogrel increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[24]
Sodium acetate anhydrous	DMH21E0	Approved	Sodium acetate anhydrous increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[31]
Clemizole	DM4UAPD	Phase 1	Clemizole increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[33]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[26]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[9]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[34]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[35]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[36]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[36]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[36]
P-Coumaric Acid	DMGJSVD	Investigative	P-Coumaric Acid decreases the activity of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[37]
CITCO	DM0N634	Investigative	CITCO decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[14]
BETULIN	DMGQRON	Investigative	BETULIN increases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[38]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re decreases the expression of Phosphoenolpyruvate carboxykinase, cytosolic (PCK1).	[39]

References

• [1] Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Mol Cell Biol. 2000 Sep;20(17):6508-17. doi: 10.1128/MCB.20.17.6508-6517.2000.
• [2] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically. Clin Transl Med. 2021 Feb;11(2):e335. doi: 10.1002/ctm2.335.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [13] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [14] Potential role of estradiol and progesterone in insulin resistance through constitutive androstane receptor. J Mol Endocrinol. 2011 Sep 7;47(2):229-39.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [17] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [18] Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes. Biochimie. 2003 Dec;85(12):1257-64. doi: 10.1016/j.biochi.2003.10.016.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [21] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [22] Expression dynamics of pregnane X receptor-controlled genes in 3D primary human hepatocyte spheroids. Arch Toxicol. 2022 Jan;96(1):195-210. doi: 10.1007/s00204-021-03177-y. Epub 2021 Oct 23.
• [23] Similarities and differences between two modes of antagonism of the thyroid hormone receptor. ACS Chem Biol. 2011 Oct 21;6(10):1096-106.
• [24] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [25] Teriflunomide is an indirect human constitutive androstane receptor (CAR) activator interacting with epidermal growth factor (EGF) signaling. Front Pharmacol. 2018 Oct 11;9:993.
• [26] Transcriptional Regulation of Human Arylamine N-Acetyltransferase 2 Gene by Glucose and Insulin in Liver Cancer Cell Lines. Toxicol Sci. 2022 Nov 23;190(2):158-172. doi: 10.1093/toxsci/kfac103.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [29] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [30] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [33] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [34] Heterocyclic amines reduce insulin-induced AKT phosphorylation and induce gluconeogenic gene expression in human hepatocytes. Arch Toxicol. 2023 Jun;97(6):1613-1626. doi: 10.1007/s00204-023-03488-2. Epub 2023 Apr 2.
• [35] Combined cytotoxicity of phthalate esters on HepG2 cells: A comprehensive analysis of transcriptomics and metabolomics. Food Chem Toxicol. 2023 Oct;180:114034. doi: 10.1016/j.fct.2023.114034. Epub 2023 Sep 12.
• [36] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [37] Procyanidin B1 and p-Coumaric Acid from Highland Barley Grain Showed Synergistic Effect on Modulating Glucose Metabolism via IRS-1/PI3K/Akt Pathway. Mol Nutr Food Res. 2021 Sep;65(18):e2100454. doi: 10.1002/mnfr.202100454. Epub 2021 Aug 16.
• [38] Anti-inflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator. Food Chem Toxicol. 2021 Nov;157:112539. doi: 10.1016/j.fct.2021.112539. Epub 2021 Sep 7.
• [39] Ginsenoside Re lowers blood glucose and lipid levels via activation of AMP-activated protein kinase in HepG2 cells and high-fat diet fed mice. Int J Mol Med. 2012 Jan;29(1):73-80. doi: 10.3892/ijmm.2011.805. Epub 2011 Oct 3.