Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQY23P)

• DOT Name: Threonine--tRNA ligase, mitochondrial (TARS2)
• Synonyms: EC 6.1.1.3; Threonyl-tRNA synthetase; ThrRS; Threonyl-tRNA synthetase-like 1
• Gene Name: TARS2
• Related Disease:
  Combined oxidative phosphorylation defect type 21
  Epilepsy
  Idiopathic inflammatory myopathy
  Influenza
  Isolated congenital microcephaly
  Mitochondrial encephalomyopathy
  Visceral leishmaniasis
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Leigh syndrome
• UniProt ID: SYTM_HUMAN
• EC Number: 6.1.1.3
• Pfam ID: PF03129 ; PF02824 ; PF00587 ; PF07973
• Sequence:
  MALYQRWRCLRLQGLQACRLHTAVVSTPPRWLAERLGLFEELWAAQVKRLASMAQKEPRT
  IKISLPGGQKIDAVAWNTTPYQLARQISSTLADTAVAAQVNGEPYDLERPLETDSDLRFL
  TFDSPEGKAVFWHSSTHVLGAAAEQFLGAVLCRGPSTEYGFYHDFFLGKERTIRGSELPV
  LERICQELTAAARPFRRLEASRDQLRQLFKDNPFKLHLIEEKVTGPTATVYGCGTLVDLC
  QGPHLRHTGQIGGLKLLSNSSSLWRSSGAPETLQRVSGISFPTTELLRVWEAWREEAELR
  DHRRIGKEQELFFFHELSPGSCFFLPRGTRVYNALVAFIRAEYAHRGFSEVKTPTLFSTK
  LWEQSGHWEHYQEDMFAVQPPGSDRPPSSQSDDSTRHITDTLALKPMNCPAHCLMFAHRP
  RSWRELPLRLADFGALHRAEASGGLGGLTRLRCFQQDDAHIFCTTDQLEAEIQSCLDFLR
  SVYAVLGFSFRLALSTRPSGFLGDPCLWDQAEQVLKQALKEFGEPWDLNSGDGAFYGPKI
  DVHLHDALGRPHQCGTIQLDFQLPLRFDLQYKGQAGALERPVLIHRAVLGSVERLLGVLA
  ESCGGKWPLWLSPFQVVVIPVGSEQEEYAKEAQQSLRAAGLVSDLDADSGLTLSRRIRRA
  QLAHYNFQFVVGQKEQSKRTVNIRTRDNRRLGEWDLPEAVQRLVELQNTRVPNAEEIF
• 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.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation defect type 21	DISC5W3K	Strong	Autosomal recessive	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[2]
Influenza	DIS3PNU3	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[1]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[4]
Visceral leishmaniasis	DISTKEYK	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Disputed	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Disputed	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Disputed	Altered Expression	[6]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[7]

8 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 Threonine--tRNA ligase, mitochondrial (TARS2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Threonine--tRNA ligase, mitochondrial (TARS2).	[16]

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 affects the methylation of Threonine--tRNA ligase, mitochondrial (TARS2).	[13]

References

• [1] VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Hum Mutat. 2014 Aug;35(8):983-9. doi: 10.1002/humu.22590. Epub 2014 Jun 24.
• [2] Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies.Medicine (Baltimore). 2006 Mar;85(2):111-127. doi: 10.1097/01.md.0000217525.82287.eb.
• [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] A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects.J Biol Chem. 2016 Mar 18;291(12):6507-20. doi: 10.1074/jbc.M115.700849. Epub 2016 Jan 25.
• [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] 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.
• [7] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.