Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2X9YO1)

• DOT Name: CTP synthase 2 (CTPS2)
• Synonyms: EC 6.3.4.2; CTP synthetase 2; UTP--ammonia ligase 2
• Gene Name: CTPS2
• Related Disease:
  Bone osteosarcoma
  Colorectal carcinoma
  Osteosarcoma
  Immunodeficiency
• UniProt ID: PYRG2_HUMAN
• PDB ID: 2V4U; 2VKT; 3IHL; 6PK4; 6PK7; 7MH1; 7MIH; 7MII
• EC Number: 6.3.4.2
• Pfam ID: PF06418 ; PF00117
• Sequence:
  MKYILVTGGVISGIGKGIIASSIGTILKSCGLRVTAIKIDPYINIDAGTFSPYEHGEVFV
  LNDGGEVDLDLGNYERFLDINLYKDNNITTGKIYQHVINKERRGDYLGKTVQVVPHITDA
  VQEWVMNQAKVPVDGNKEEPQICVIELGGTIGDIEGMPFVEAFRQFQFKAKRENFCNIHV
  SLVPQLSATGEQKTKPTQNSVRALRGLGLSPDLIVCRSSTPIEMAVKEKISMFCHVNPEQ
  VICIHDVSSTYRVPVLLEEQSIVKYFKERLHLPIGDSASNLLFKWRNMADRYERLQKICS
  IALVGKYTKLRDCYASVFKALEHSALAINHKLNLMYIDSIDLEKITETEDPVKFHEAWQK
  LCKADGILVPGGFGIRGTLGKLQAISWARTKKIPFLGVCLGMQLAVIEFARNCLNLKDAD
  STEFRPNAPVPLVIDMPEHNPGNLGGTMRLGIRRTVFKTENSILRKLYGDVPFIEERHRH
  RFEVNPNLIKQFEQNDLSFVGQDVDGDRMEIIELANHPYFVGVQFHPEFSSRPMKPSPPY
  LGLLLAATGNLNAYLQQGCKLSSSDRYSDASDDSFSEPRIAELEIS
• Function: Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Constitutes the rate-limiting enzyme in the synthesis of cytosine nucleotides.
• 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:HS00585-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Altered Expression	[2]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[3]

13 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 2 (CTPS2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CTP synthase 2 (CTPS2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of CTP synthase 2 (CTPS2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CTP synthase 2 (CTPS2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CTP synthase 2 (CTPS2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CTP synthase 2 (CTPS2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CTP synthase 2 (CTPS2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of CTP synthase 2 (CTPS2).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of CTP synthase 2 (CTPS2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of CTP synthase 2 (CTPS2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of CTP synthase 2 (CTPS2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CTP synthase 2 (CTPS2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CTP synthase 2 (CTPS2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of CTP synthase 2 (CTPS2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CTP synthase 2 (CTPS2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of CTP synthase 2 (CTPS2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of CTP synthase 2 (CTPS2).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of CTP synthase 2 (CTPS2).	[14]

References

• [1] Identification of critical genes associated with human osteosarcoma metastasis based on integrated gene expression profiling.Mol Med Rep. 2019 Aug;20(2):915-930. doi: 10.3892/mmr.2019.10323. Epub 2019 Jun 3.
• [2] Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer.Cancer Biol Ther. 2011 Mar 15;11(6):599-608. doi: 10.4161/cbt.11.6.14670. Epub 2011 Mar 15.
• [3] The Challenge of Next Generation Sequencing in a Boy With Severe Mononucleosis and EBV-related Lymphoma.J Pediatr Hematol Oncol. 2018 Jul;40(5):e323-e326. doi: 10.1097/MPH.0000000000001004.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] 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.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] 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.
• [18] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.