Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ9J6ZG)

• DOT Name: CTP synthase 1 (CTPS1)
• Synonyms: EC 6.3.4.2; CTP synthetase 1; UTP--ammonia ligase 1
• Gene Name: CTPS1
• Related Disease: Severe combined immunodeficiency due to CTPS1 deficiency
• UniProt ID: PYRG1_HUMAN
• PDB ID: 2VO1; 5U03; 7MGZ; 7MH0; 7MIF; 7MIG
• EC Number: 6.3.4.2
• Pfam ID: PF06418 ; PF00117
• Sequence:
  MKYILVTGGVISGIGKGIIASSVGTILKSCGLHVTSIKIDPYINIDAGTFSPYEHGEVFV
  LDDGGEVDLDLGNYERFLDIRLTKDNNLTTGKIYQYVINKERKGDYLGKTVQVVPHITDA
  IQEWVMRQALIPVDEDGLEPQVCVIELGGTVGDIESMPFIEAFRQFQFKVKRENFCNIHV
  SLVPQPSSTGEQKTKPTQNSVRELRGLGLSPDLVVCRCSNPLDTSVKEKISMFCHVEPEQ
  VICVHDVSSIYRVPLLLEEQGVVDYFLRRLDLPIERQPRKMLMKWKEMADRYDRLLETCS
  IALVGKYTKFSDSYASVIKALEHSALAINHKLEIKYIDSADLEPITSQEEPVRYHEAWQK
  LCSAHGVLVPGGFGVRGTEGKIQAIAWARNQKKPFLGVCLGMQLAVVEFSRNVLGWQDAN
  STEFDPTTSHPVVVDMPEHNPGQMGGTMRLGKRRTLFQTKNSVMRKLYGDADYLEERHRH
  RFEVNPVWKKCLEEQGLKFVGQDVEGERMEIVELEDHPFFVGVQYHPEFLSRPIKPSPPY
  FGLLLASVGRLSHYLQKGCRLSPRDTYSDRSGSSSPDSEITELKFPSINHD
• Function: This enzyme is involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids. Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as a source of nitrogen. This enzyme and its product, CTP, play a crucial role in the proliferation of activated lymphocytes and therefore in immunity.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Interconversion of nucleotide di- and triphosphates (R-HSA-499943)
• BioCyc Pathway: MetaCyc:HS10382-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe combined immunodeficiency due to CTPS1 deficiency	DIS0NS7C	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of CTP synthase 1 (CTPS1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CTP synthase 1 (CTPS1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of CTP synthase 1 (CTPS1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CTP synthase 1 (CTPS1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CTP synthase 1 (CTPS1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of CTP synthase 1 (CTPS1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of CTP synthase 1 (CTPS1).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of CTP synthase 1 (CTPS1).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of CTP synthase 1 (CTPS1).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of CTP synthase 1 (CTPS1).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of CTP synthase 1 (CTPS1).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of CTP synthase 1 (CTPS1).	[11]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of CTP synthase 1 (CTPS1).	[12]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of CTP synthase 1 (CTPS1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of CTP synthase 1 (CTPS1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CTP synthase 1 (CTPS1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CTP synthase 1 (CTPS1).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of CTP synthase 1 (CTPS1).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of CTP synthase 1 (CTPS1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CTP synthase 1 (CTPS1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of CTP synthase 1 (CTPS1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of CTP synthase 1 (CTPS1).	[14]

References

• [1] CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature. 2014 Jun 12;510(7504):288-92. doi: 10.1038/nature13386. Epub 2014 May 28.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] 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.
• [4] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [5] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [11] Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009 Sep;20(8):682-92.
• [12] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.