Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG81SGD)

• DOT Name: Tyrosine--tRNA ligase, cytoplasmic
• Synonyms: EC 6.1.1.1; Tyrosyl-tRNA synthetase; TyrRS
• Gene Name: YARS1
• Related Disease:
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease dominant intermediate C
  Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
• UniProt ID: SYYC_HUMAN
• PDB ID: 1N3L; 1NTG; 1Q11; 4Q93; 4QBT; 5THH; 5THL; 7ROU
• EC Number: 6.1.1.1
• Pfam ID: PF00579 ; PF01588
• Sequence:
  MGDAPSPEEKLHLITRNLQEVLGEEKLKEILKERELKIYWGTATTGKPHVAYFVPMSKIA
  DFLKAGCEVTILFADLHAYLDNMKAPWELLELRVSYYENVIKAMLESIGVPLEKLKFIKG
  TDYQLSKEYTLDVYRLSSVVTQHDSKKAGAEVVKQVEHPLLSGLLYPGLQALDEEYLKVD
  AQFGGIDQRKIFTFAEKYLPALGYSKRVHLMNPMVPGLTGSKMSSSEEESKIDLLDRKED
  VKKKLKKAFCEPGNVENNGVLSFIKHVLFPLKSEFVILRDEKWGGNKTYTAYVDLEKDFA
  AEVVHPGDLKNSVEVALNKLLDPIREKFNTPALKKLASAAYPDPSKQKPMAKGPAKNSEP
  EEVIPSRLDIRVGKIITVEKHPDADSLYVEKIDVGEAEPRTVVSGLVQFVPKEELQDRLV
  VVLCNLKPQKMRGVESQGMLLCASIEGINRQVEPLDPPAGSAPGEHVFVKGYEKGQPDEE
  LKPKKKVFEKLQADFKISEECIAQWKQTNFMTKLGSISCKSLKGGNIS
• Function: Tyrosine--tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr) (Probable). Also acts as a positive regulator of poly-ADP-ribosylation in the nucleus, independently of its tyrosine--tRNA ligase activity. Activity is switched upon resveratrol-binding: resveratrol strongly inhibits the tyrosine--tRNA ligase activity and promotes relocalization to the nucleus, where YARS1 specifically stimulates the poly-ADP-ribosyltransferase activity of PARP1.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Definitive	Autosomal dominant	[1]
Charcot-Marie-Tooth disease dominant intermediate C	DISG03UJ	Strong	Autosomal dominant	[2]
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2	DISKMOUS	Strong	Autosomal recessive	[3]

1 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 Tyrosine--tRNA ligase, cytoplasmic.	[4]

23 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 Tyrosine--tRNA ligase, cytoplasmic.	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tyrosine--tRNA ligase, cytoplasmic.	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[11]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[19]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Tyrosine--tRNA ligase, cytoplasmic.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Tyrosine--tRNA ligase, cytoplasmic.	[12]

References

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• [2] Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet. 2006 Feb;38(2):197-202. doi: 10.1038/ng1727. Epub 2006 Jan 22.
• [3] A novel multisystem disease associated with recessive mutations in the tyrosyl-tRNA synthetase (YARS) gene. Am J Med Genet A. 2017 Jan;173(1):126-134. doi: 10.1002/ajmg.a.37973. Epub 2016 Sep 15.
• [4] 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.
• [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] 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.
• [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] 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.
• [11] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [12] A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature. 2015 Mar 19;519(7543):370-3. doi: 10.1038/nature14028. Epub 2014 Dec 22.
• [13] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [19] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [20] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.