Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNCJKY7)

• DOT Name: Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2)
• Synonyms: EC 6.1.1.24; Glutamate--tRNA(Gln) ligase EARS2, mitochondrial; EC 6.1.1.17; Glutamyl-tRNA synthetase; GluRS; Mitochondrial glutamyl-tRNA synthetase; mtGluRS
• Gene Name: EARS2
• Related Disease:
  Leigh syndrome
  Myocardial infarction
  Corpus callosum, agenesis of
  Epilepsy
  Graves disease
  Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
  Major depressive disorder
  Niemann-Pick disease, type C1
  Systemic lupus erythematosus
  Ulcerative colitis
  Coronary atherosclerosis
  Coronary heart disease
  Hashimoto thyroiditis
  Arteriosclerosis
  Atherosclerosis
  Lactic acidosis
• UniProt ID: SYEM_HUMAN
• EC Number: 6.1.1.17; 6.1.1.24
• Pfam ID: PF19269 ; PF00749
• Sequence:
  MAALLRRLLQRERPSAASGRPVGRREANLGTDAGVAVRVRFAPSPTGFLHLGGLRTALYN
  YIFAKKYQGSFILRLEDTDQTRVVPGAAENIEDMLEWAGIPPDESPRRGGPAGPYQQSQR
  LELYAQATEALLKTGAAYPCFCSPQRLELLKKEALRNHQTPRYDNRCRNMSQEQVAQKLA
  KDPKPAIRFRLEQVVPAFQDLVYGWNRHEVASVEGDPVIMKSDGFPTYHLACVVDDHHMG
  ISHVLRGSEWLVSTAKHLLLYQALGWQPPHFAHLPLLLNRDGSKLSKRQGDVFLEHFAAD
  GFLPDSLLDIITNCGSGFAENQMGRTLPELITQFNLTQVTCHSALLDLEKLPEFNRLHLQ
  RLVSNESQRRQLVGKLQVLVEEAFGCQLQNRDVLNPVYVERILLLRQGHICRLQDLVSPV
  YSYLWTRPAVGRAQLDAISEKVDVIAKRVLGLLERSSMSLTQDMLNGELKKLSEGLEGTK
  YSNVMKLLRMALSGQQQGPPVAEMMLALGPKEVRERIQKVVSS
• Function: Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation. Attachs glutamate to tRNA(Glu) or tRNA(Gln) in a two-step reaction: glutamate is first activated by ATP to form Glu-AMP and then transferred to the acceptor end of tRNA(Glu) or tRNA(Gln). In vitro, cytoplasmic tRNA(Gln) is slightly glutamylated, but with low activity.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Aminoacyl-tR. biosynthesis (hsa00970)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Myocardial infarction	DIS655KI	Definitive	Biomarker	[2]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Graves disease	DISU4KOQ	Strong	Biomarker	[5]
Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	DISTJRZV	Strong	Autosomal recessive	[4]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[6]
Niemann-Pick disease, type C1	DIS9HUE3	Strong	Biomarker	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[5]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[8]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[9]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[9]
Hashimoto thyroiditis	DIS77CDF	moderate	Genetic Variation	[10]
Arteriosclerosis	DISK5QGC	Limited	Genetic Variation	[9]
Atherosclerosis	DISMN9J3	Limited	Genetic Variation	[9]
Lactic acidosis	DISZI1ZK	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[18]

10 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 Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[20]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial (EARS2).	[22]

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] Effect of apo E phenotype on plasma postprandial triglyceride levels in young male adults with and without a familial history of myocardial infarction: the EARS II study. European Atherosclerosis Research Study.Atherosclerosis. 1999 Aug;145(2):381-8. doi: 10.1016/s0021-9150(99)00069-6.
• [3] EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.Metab Brain Dis. 2016 Jun;31(3):717-21. doi: 10.1007/s11011-016-9793-2. Epub 2016 Jan 16.
• [4] Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations. Brain. 2012 May;135(Pt 5):1387-94. doi: 10.1093/brain/aws070. Epub 2012 Apr 4.
• [5] No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies.Clin Endocrinol (Oxf). 1998 Sep;49(3):331-4. doi: 10.1046/j.1365-2265.1998.00542.x.
• [6] Sex differences in glutamate receptor gene expression in major depression and suicide.Mol Psychiatry. 2015 Sep;20(9):1057-68. doi: 10.1038/mp.2015.91. Epub 2015 Jul 14.
• [7] Decreased calcium flux in Niemann-Pick type C1 patient-specific iPSC-derived neurons due to higher amount of calcium-impermeable AMPA receptors.Mol Cell Neurosci. 2017 Sep;83:27-36. doi: 10.1016/j.mcn.2017.06.007. Epub 2017 Jun 27.
• [8] Impact of Histological and Endoscopic Remissions on Clinical Recurrence and Recurrence-free Time in Ulcerative Colitis.Inflamm Bowel Dis. 2017 Dec;23(12):2238-2244. doi: 10.1097/MIB.0000000000001275.
• [9] Postprandial response to a fat tolerance test in young adults with a paternal history of premature coronary heart disease - the EARS II study (European Atherosclerosis Research Study).Eur J Clin Invest. 2000 Jul;30(7):578-85. doi: 10.1046/j.1365-2362.2000.00674.x.
• [10] Cytotoxic T-lymphocyte antigen-4 gene polymorphisms and human T-cell lymphotrophic virus-1 infection: their associations with Hashimoto's thyroiditis in Japanese patients.Thyroid. 2002 Aug;12(8):673-7. doi: 10.1089/105072502760258640.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] 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.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [22] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.