Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0PWST5)

• DOT Name: Threonine--tRNA ligase 1, cytoplasmic (TARS1)
• Synonyms: EC 6.1.1.3; Threonyl-tRNA synthetase; ThrRS; Threonyl-tRNA synthetase 1
• Gene Name: TARS1
• Related Disease:
  Idiopathic inflammatory myopathy
  Adult T-cell leukemia/lymphoma
  Infectious myositis
  Influenza
  Myositis disease
  T-cell leukaemia
  Visceral leishmaniasis
  Trichothiodystrophy
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: SYTC_HUMAN
• PDB ID: 1WWT; 4HWT; 4P3N; 4TTV; 5XLN
• EC Number: 6.1.1.3
• Pfam ID: PF03129 ; PF02824 ; PF00587 ; PF07973
• Sequence:
  MFEEKASSPSGKMGGEEKPIGAGEEKQKEGGKKKNKEGSGDGGRAELNPWPEYIYTRLEM
  YNILKAEHDSILAEKAEKDSKPIKVTLPDGKQVDAESWKTTPYQIACGISQGLADNTVIA
  KVNNVVWDLDRPLEEDCTLELLKFEDEEAQAVYWHSSAHIMGEAMERVYGGCLCYGPPIE
  NGFYYDMYLEEGGVSSNDFSSLEALCKKIIKEKQAFERLEVKKETLLAMFKYNKFKCRIL
  NEKVNTPTTTVYRCGPLIDLCRGPHVRHTGKIKALKIHKNSSTYWEGKADMETLQRIYGI
  SFPDPKMLKEWEKFQEEAKNRDHRKIGRDQELYFFHELSPGSCFFLPKGAYIYNALIEFI
  RSEYRKRGFQEVVTPNIFNSRLWMTSGHWQHYSENMFSFEVEKELFALKPMNCPGHCLMF
  DHRPRSWRELPLRLADFGVLHRNELSGALTGLTRVRRFQQDDAHIFCAMEQIEDEIKGCL
  DFLRTVYSVFGFSFKLNLSTRPEKFLGDIEVWDQAEKQLENSLNEFGEKWELNSGDGAFY
  GPKIDIQIKDAIGRYHQCATIQLDFQLPIRFNLTYVSHDGDDKKRPVIVHRAILGSVERM
  IAILTENYGGKWPFWLSPRQVMVVPVGPTCDEYAQKVRQQFHDAKFMADIDLDPGCTLNK
  KIRNAQLAQYNFILVVGEKEKISGTVNIRTRDNKVHGERTISETIERLQQLKEFRSKQAE
  EEF
• Function: Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr). Also edits incorrectly charged tRNA(Thr) via its editing domain, at the post-transfer stage.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Idiopathic inflammatory myopathy	DISGB1BZ	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Infectious myositis	DISD09ET	Strong	Biomarker	[1]
Influenza	DIS3PNU3	Strong	Genetic Variation	[3]
Myositis disease	DISCIXF0	Strong	Biomarker	[1]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[4]
Visceral leishmaniasis	DISTKEYK	Strong	Biomarker	[5]
Trichothiodystrophy	DISOMQD2	Supportive	Autosomal recessive	[6]
Epithelial ovarian cancer	DIS56MH2	Disputed	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Disputed	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Disputed	Altered Expression	[7]

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 Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[19]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[20]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[20]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[20]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[18]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[28]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[30]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[31]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[32]
Borrelidin	DMBSQTR	Investigative	Borrelidin decreases the activity of Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[33]

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 Threonine--tRNA ligase 1, cytoplasmic (TARS1).	[22]

References

• [1] Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis.Sci Rep. 2013;3:1317. doi: 10.1038/srep01317.
• [2] TCGF(IL 2)-receptor inducing factor(s). II. Possible role of ATL-derived factor (ADF) on constitutive IL 2 receptor expression of HTLV-I(+) T cell lines.J Immunol. 1985 Dec;135(6):3995-4003.
• [3] On the nature and use of randomly amplified DNA from Staphylococcus aureus.J Clin Microbiol. 1996 Nov;34(11):2770-7. doi: 10.1128/jcm.34.11.2770-2777.1996.
• [4] Rat lymphoid cell lines with human T cell leukemia virus production. I. Biological and serological characterization.J Exp Med. 1984 Apr 1;159(4):1105-16. doi: 10.1084/jem.159.4.1105.
• [5] Genetic manipulation of Leishmania donovani threonyl tRNA synthetase facilitates its exploration as a potential therapeutic target.PLoS Negl Trop Dis. 2018 Jun 13;12(6):e0006575. doi: 10.1371/journal.pntd.0006575. eCollection 2018 Jun.
• [6] Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Am J Hum Genet. 2019 Aug 1;105(2):434-440. doi: 10.1016/j.ajhg.2019.06.017.
• [7] Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer.BMC Cancer. 2014 Aug 27;14:620. doi: 10.1186/1471-2407-14-620.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [14] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [15] 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.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] 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.
• [18] 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.
• [19] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [20] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [21] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] 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.
• [26] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [27] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [28] 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.
• [29] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [30] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [31] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
• [32] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.
• [33] Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5508-17. doi: 10.1073/pnas.1405994111. Epub 2014 Dec 8.