Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT16G0TR)

• DOT Name: Tyrosine--tRNA ligase, mitochondrial
• Synonyms: EC 6.1.1.1; Tyrosyl-tRNA synthetase; TyrRS
• Gene Name: YARS2
• Related Disease:
  Myopathy, lactic acidosis, and sideroblastic anemia 2
  Myopathy, lactic acidosis, and sideroblastic anemia
• UniProt ID: SYYM_HUMAN
• PDB ID: 2PID; 3ZXI
• EC Number: 6.1.1.1
• Pfam ID: PF00579
• Sequence:
  MAAPILRSFSWGRWSGTLNLSVLLPLGLRKAHSGAQGLLAAQKARGLFKDFFPETGTKIE
  LPELFDRGTASFPQTIYCGFDPTADSLHVGHLLALLGLFHLQRAGHNVIALVGGATARLG
  DPSGRTKEREALETERVRANARALRLGLEALAANHQQLFTDGRSWGSFTVLDNSAWYQKQ
  HLVDFLAAVGGHFRMGTLLSRQSVQLRLKSPEGMSLAEFFYQVLQAYDFYYLFQRYGCRV
  QLGGSDQLGNIMSGYEFINKLTGEDVFGITVPLITSTTGAKLGKSAGNAVWLNRDKTSPF
  ELYQFFVRQPDDSVERYLKLFTFLPLPEIDHIMQLHVKEPERRGPQKRLAAEVTKLVHGR
  EGLDSAKRCTQALYHSSIDALEVMSDQELKELFKEAPFSEFFLDPGTSVLDTCRKANAIP
  DGPRGYRMITEGGVSINHQQVTNPESVLIVGQHILKNGLSLLKIGKRNFYIIKWLQL
• Function: 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).
• 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
Myopathy, lactic acidosis, and sideroblastic anemia 2	DISX8JWC	Definitive	Autosomal recessive	[1]
Myopathy, lactic acidosis, and sideroblastic anemia	DISGW7N3	Supportive	Autosomal recessive	[2]

13 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 Tyrosine--tRNA ligase, mitochondrial.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tyrosine--tRNA ligase, mitochondrial.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tyrosine--tRNA ligase, mitochondrial.	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Tyrosine--tRNA ligase, mitochondrial.	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[11]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose increases the expression of Tyrosine--tRNA ligase, mitochondrial.	[10]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Tyrosine--tRNA ligase, mitochondrial.	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Tyrosine--tRNA ligase, mitochondrial.	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tyrosine--tRNA ligase, mitochondrial.	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tyrosine--tRNA ligase, mitochondrial.	[13]

References

• [1] The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. Haematologica. 2018 Dec;103(12):2008-2015. doi: 10.3324/haematol.2017.182659. Epub 2018 Jul 19.
• [2] Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. Am J Hum Genet. 2010 Jul 9;87(1):52-9. doi: 10.1016/j.ajhg.2010.06.001.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [10] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.