Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68H24R)

• DOT Name: Tryptophan--tRNA ligase, mitochondrial
• Synonyms: EC 6.1.1.2; (Mt)TrpRS; Tryptophanyl-tRNA synthetase; TrpRS
• Gene Name: WARS2
• Related Disease:
  Mitochondrial disease
  Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
• UniProt ID: SYWM_HUMAN
• PDB ID: 5EKD
• EC Number: 6.1.1.2
• Pfam ID: PF00579
• Sequence:
  MALHSMRKARERWSFIRALHKGSAAAPALQKDSKKRVFSGIQPTGILHLGNYLGAIESWV
  RLQDEYDSVLYSIVDLHSITVPQDPAVLRQSILDMTAVLLACGINPEKSILFQQSQVSEH
  TQLSWILSCMVRLPRLQHLHQWKAKTTKQKHDGTVGLLTYPVLQAADILLYKSTHVPVGE
  DQVQHMELVQDLAQGFNKKYGEFFPVPESILTSMKKVKSLRDPSAKMSKSDPDKLATVRI
  TDSPEEIVQKFRKAVTDFTSEVTYDPAGRAGVSNIVAVHAAVTGLSVEEVVRRSAGMNTA
  RYKLAVADAVIEKFAPIKREIEKLKLDKDHLEKVLQIGSAKAKELAYTVCQEVKKLVGFL
• Function: Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of tRNA(Trp).
• Tissue Specificity: Brain.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures	DISFF60A	Strong	Autosomal recessive	[2]

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 Tryptophan--tRNA ligase, mitochondrial.	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Tryptophan--tRNA ligase, mitochondrial.	[8]

9 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 Tryptophan--tRNA ligase, mitochondrial.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tryptophan--tRNA ligase, mitochondrial.	[9]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Tryptophan--tRNA ligase, mitochondrial.	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tryptophan--tRNA ligase, mitochondrial.	[13]

References

• [1] 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.
• [2] Prevention of atopic dermatitis. F1000 Med Rep. 2012;4:24. doi: 10.3410/M4-24. Epub 2012 Dec 3.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [7] 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.
• [8] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.