Details of Drug Off-Target (DOT)

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

• DOT Name: Thymidylate kinase (DTYMK)
• Synonyms: EC 2.7.4.9; dTMP kinase
• Gene Name: DTYMK
• Related Disease:
  Neurodegeneration, childhood-onset, with progressive microcephaly
  Mitochondrial DNA depletion syndrome
• UniProt ID: KTHY_HUMAN
• PDB ID: 1E2D; 1E2E; 1E2F; 1E2G; 1E2Q; 1E98; 1E99; 1E9A; 1E9B; 1E9C; 1E9D; 1E9E; 1E9F; 1NMX; 1NMY; 1NMZ; 1NN0; 1NN1; 1NN3; 1NN5; 2XX3
• EC Number: 2.7.4.9
• Pfam ID: PF02223
• Sequence:
  MAARRGALIVLEGVDRAGKSTQSRKLVEALCAAGHRAELLRFPERSTEIGKLLSSYLQKK
  SDVEDHSVHLLFSANRWEQVPLIKEKLSQGVTLVVDRYAFSGVAFTGAKENFSLDWCKQP
  DVGLPKPDLVLFLQLQLADAAKRGAFGHERYENGAFQERALRCFHQLMKDTTLNWKMVDA
  SKSIEAVHEDIRVLSEDAIRTATEKPLGELWK
• Function: Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP, with ATP as the preferred phosphoryl donor in the presence of Mg(2+).
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Interconversion of nucleotide di- and triphosphates (R-HSA-499943)
• BioCyc Pathway: MetaCyc:HS11626-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
Neurodegeneration, childhood-onset, with progressive microcephaly	DISYXAK6	Strong	Autosomal recessive	[1]
Mitochondrial DNA depletion syndrome	DISIGZSM	Limited	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Thymidylate kinase (DTYMK) affects the response to substance of Doxorubicin.	[25]
Zidovudine	DM4KI7O	Approved	Thymidylate kinase (DTYMK) affects the response to substance of Zidovudine.	[26]

24 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 Thymidylate kinase (DTYMK).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Thymidylate kinase (DTYMK).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thymidylate kinase (DTYMK).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Thymidylate kinase (DTYMK).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Thymidylate kinase (DTYMK).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Thymidylate kinase (DTYMK).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thymidylate kinase (DTYMK).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thymidylate kinase (DTYMK).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Thymidylate kinase (DTYMK).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Thymidylate kinase (DTYMK).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thymidylate kinase (DTYMK).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Thymidylate kinase (DTYMK).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Thymidylate kinase (DTYMK).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Thymidylate kinase (DTYMK).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Thymidylate kinase (DTYMK).	[12]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Thymidylate kinase (DTYMK).	[16]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Thymidylate kinase (DTYMK).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thymidylate kinase (DTYMK).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Thymidylate kinase (DTYMK).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Thymidylate kinase (DTYMK).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Thymidylate kinase (DTYMK).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Thymidylate kinase (DTYMK).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thymidylate kinase (DTYMK).	[23]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Thymidylate kinase (DTYMK).	[24]

1 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 Thymidylate kinase (DTYMK).	[20]

References

• [1] Deoxythymidylate kinase, DTYMK, is a novel gene for mitochondrial DNA depletion syndrome. Clin Chim Acta. 2019 Sep;496:93-99. doi: 10.1016/j.cca.2019.06.028. Epub 2019 Jul 2.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [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] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Comparison of gene expression in HCT116 treatment derivatives generated by two different 5-fluorouracil exposure protocols. Mol Cancer. 2004 Apr 26;3:11.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [17] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Impact of epigallocatechin gallate on gene expression profiles of human hepatocellular carcinoma cell lines BEL7404/ADM and BEL7402/5-FU. Ai Zheng. 2008 Oct;27(10):1056-64.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [24] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [25] Synthetic lethality by lentiviral short hairpin RNA silencing of thymidylate kinase and doxorubicin in colon cancer cells regardless of the p53 status. Cancer Res. 2008 Apr 15;68(8):2831-40. doi: 10.1158/0008-5472.CAN-07-3069.
• [26] Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system. Redox Biol. 2017 Oct;13:407-417.