Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL5X535)

• DOT Name: Asparaginyl-tRNA synthetase (NARS2)
• Synonyms: AsnRS; NARS2; EC 6.1.1.22; Asparagine--tRNA ligase, mitochondrial
• Gene Name: NARS2
• Related Disease:
  Epilepsy
  Alzheimer disease
  Combined oxidative phosphorylation defect type 24
  Mitochondrial DNA depletion syndrome 4a
  Myopathy
  Mitochondrial disease
  Hearing loss, autosomal recessive
  Hearing loss, autosomal recessive 94
  Leigh syndrome
  Nonsyndromic genetic hearing loss
• UniProt ID: SYNM_HUMAN
• EC Number: 6.1.1.22
• Pfam ID: PF00152 ; PF01336
• Sequence:
  MLGVRCLLRSVRFCSSAPFPKHKPSAKLSVRDALGAQNASGERIKIQGWIRSVRSQKEVL
  FLHVNDGSSLESLQVVADSGLDSRELNFGSSVEVQGQLIKSPSKRQNVELKAEKIKVIGN
  CDAKDFPIKYKERHPLEYLRQYPHFRCRTNVLGSILRIRSEATAAIHSFFKDSGFVHIHT
  PIITSNDSEGAGELFQLEPSGKLKVPEENFFNVPAFLTVSGQLHLEVMSGAFTQVFTFGP
  TFRAENSQSRRHLAEFYMIEAEISFVDSLQDLMQVIEELFKATTMMVLSKCPEDVELCHK
  FIAPGQKDRLEHMLKNNFLIISYTEAVEILKQASQNFTFTPEWGADLRTEHEKYLVKHCG
  NIPVFVINYPLTLKPFYMRDNEDGPQHTVAAVDLLVPGVGELFGGGLREERYHFLEERLA
  RSGLTEVYQWYLDLRRFGSVPHGGFGMGFERYLQCILGVDNIKDVIPFPRFPHSCLL
• Function: Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis. The reaction occurs in a two steps: asparagine is first activated by ATP to form Asn-AMP and then transferred to the acceptor end of tRNA(Asn) (Probable).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Combined oxidative phosphorylation defect type 24	DIS8I7AX	Strong	Autosomal recessive	[3]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Strong	Genetic Variation	[4]
Myopathy	DISOWG27	Strong	Genetic Variation	[4]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[5]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]
Hearing loss, autosomal recessive 94	DIS3YGUR	Limited	Autosomal recessive	[5]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[6]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[6]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Asparaginyl-tRNA synthetase (NARS2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Asparaginyl-tRNA synthetase (NARS2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Asparaginyl-tRNA synthetase (NARS2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Asparaginyl-tRNA synthetase (NARS2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Asparaginyl-tRNA synthetase (NARS2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Asparaginyl-tRNA synthetase (NARS2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Asparaginyl-tRNA synthetase (NARS2).	[13]

References

• [1] Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy.Pediatr Neurol. 2018 Dec;89:26-30. doi: 10.1016/j.pediatrneurol.2018.07.014. Epub 2018 Aug 4.
• [2] Alzheimer's Disease Risk Variant rs2373115 Regulates GAB2 and NARS2 Expression in Human Brain Tissues.J Mol Neurosci. 2018 Sep;66(1):37-43. doi: 10.1007/s12031-018-1144-9. Epub 2018 Aug 7.
• [3] Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2). Hum Mutat. 2015 Feb;36(2):222-31. doi: 10.1002/humu.22728.
• [4] PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.J Hum Genet. 2017 Apr;62(5):525-529. doi: 10.1038/jhg.2016.163. Epub 2017 Jan 12.
• [5] Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genet. 2015 Mar 25;11(3):e1005097. doi: 10.1371/journal.pgen.1005097. eCollection 2015 Mar.
• [6] 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.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] 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.
• [17] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.