Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDX4SCA)

• DOT Name: Isoleucine--tRNA ligase, mitochondrial (IARS2)
• Synonyms: EC 6.1.1.5; Isoleucyl-tRNA synthetase; IleRS
• Gene Name: IARS2
• Related Disease:
  West syndrome
  Abdominal aortic aneurysm
  Achalasia
  Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
  Hypertrophic cardiomyopathy
  Lung neoplasm
  Non-small-cell lung cancer
  Peripheral neuropathy
  Sensorineural hearing loss disorder
  Hirschsprung disease
  Methicillin-resistant staphylococci infection
  X-linked spondyloepimetaphyseal dysplasia
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Leigh syndrome
  Mitochondrial disease
  Neoplasm
  Nervous system disease
  Stomach cancer
• UniProt ID: SYIM_HUMAN
• EC Number: 6.1.1.5
• Pfam ID: PF08264 ; PF00133 ; PF06827
• Sequence:
  MRWGLRPRGPGAAALATARSLWGTPRLPCSPGWQGATKRLLVRSVSGASNHQPNSNSGRY
  RDTVLLPQTSFPMKLLGRQQPDTELEIQQKCGFSELYSWQRERKVKTEFCLHDGPPYANG
  DPHVGHALNKILKDIANRFHMMNGSKIHFVPGWDCHGLPIEIKVLSELGREAQNLSAMEI
  RKKARSFAKAAIEKQKSAFIRWGIMADWNNCYYTFDGKYEAKQLRTFYQMYDKGLVYRSY
  KPVFWSPSSRTALAEAELEYNPEHVSRSIYVKFPLLKPSPKLASLIDGSSPVSILVWTTQ
  PWTIPANEAVCYMPESKYAVVKCSKSGDLYVLAADKVASVASTLETTFETISTLSGVDLE
  NGTCSHPLIPDKASPLLPANHVTMAKGTGLVHTAPAHGMEDYGVASQHNLPMDCLVDEDG
  VFTDVAGPELQNKAVLEEGTDVVIKMLQTAKNLLKEEKLVHSYPYDWRTKKPVVIRASKQ
  WFINITDIKTAAKELLKKVKFIPGSALNGMVEMMDRRPYWCISRQRVWGVPIPVFHHKTK
  DEYLINSQTTEHIVKLVEQHGSDIWWTLPPEQLLPKEVLSEVGGPDALEYVPGQDILDIW
  FDSGTSWSYVLPGPDQRADLYLEGKDQLGGWFQSSLLTSVAARKRAPYKTVIVHGFTLGE
  KGEKMSKSLGNVIHPDVVVNGGQDQSKEPPYGADVLRWWVADSNVFTEVAIGPSVLNAAR
  DDISKLRNTLRFLLGNVADFNPETDSIPVNDMYVIDQYMLHLLQDLANKITELYKQYDFG
  KVVRLLRTFYTRELSNFYFSIIKDRLYCEKENDPKRRSCQTALVEILDVIVRSFAPILPH
  LAEEVFQHIPYIKEPKSVFRTGWISTSSIWKKPGLEEAVESACAMRDSFLGSIPGKNAAE
  YKVITVIEPGLLFEIIEMLQSEETSSTSQLNELMMASESTLLAQEPREMTADVIELKGKF
  LINLEGGDIREESSYKVIVMPTTKEKCPRCWKYTAESSDTLCPRCAEVVSGK
• Function: Aminoacyl-tRNA synthetase that catalyzes the specific attachment of isoleucine to its cognate tRNA (tRNA(Ile)).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
West syndrome	DISLIAU9	Definitive	Biomarker	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Altered Expression	[2]
Achalasia	DISK845N	Strong	Biomarker	[1]
Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome	DISC6AZ9	Strong	Autosomal recessive	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[4]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Peripheral neuropathy	DIS7KN5G	Strong	CausalMutation	[3]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[1]
Hirschsprung disease	DISUUSM1	moderate	Altered Expression	[7]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[8]
X-linked spondyloepimetaphyseal dysplasia	DIS3O60H	moderate	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Colon cancer	DISVC52G	Limited	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[10]
Gastric cancer	DISXGOUK	Limited	Biomarker	[11]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[12]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[1]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[13]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[1]
Stomach cancer	DISKIJSX	Limited	Biomarker	[11]

9 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 Isoleucine--tRNA ligase, mitochondrial (IARS2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[18]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Isoleucine--tRNA ligase, mitochondrial (IARS2).	[22]

References

• [1] Expanding the clinical phenotype of IARS2-related mitochondrial disease.BMC Med Genet. 2018 Nov 12;19(1):196. doi: 10.1186/s12881-018-0709-3.
• [2] Up regulation of isoleucyl-tRNA synthetase promotes vascular smooth muscle cells dysfunction via p38 MAPK/PI3K signaling pathways.Life Sci. 2019 May 1;224:51-57. doi: 10.1016/j.lfs.2019.03.052. Epub 2019 Mar 21.
• [3] Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome. Hum Mutat. 2014 Nov;35(11):1285-9. doi: 10.1002/humu.22629. Epub 2014 Oct 18.
• [4] Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T>C mitochondrial tRNA(Ile) mutation causing hypertrophic cardiomyopathy.Hum Mol Genet. 2012 Jan 1;21(1):85-100. doi: 10.1093/hmg/ddr440. Epub 2011 Sep 26.
• [5] The Oncogene IARS2 Promotes Non-small Cell Lung Cancer Tumorigenesis by Activating the AKT/MTOR Pathway.Front Oncol. 2019 May 14;9:393. doi: 10.3389/fonc.2019.00393. eCollection 2019.
• [6] IARS2 silencing induces non-small cell lung cancer cells proliferation inhibition, cell cycle arrest and promotes cell apoptosis.Neoplasma. 2016;63(1):64-71. doi: 10.4149/neo_2016_008.
• [7] Role of MiR-215 in Hirschsprung's Disease Pathogenesis by Targeting SIGLEC-8.Cell Physiol Biochem. 2016;40(6):1646-1655. doi: 10.1159/000453214. Epub 2016 Dec 23.
• [8] Mupirocin: biosynthesis, special features and applications of an antibiotic from a gram-negative bacterium.Appl Microbiol Biotechnol. 2011 Apr;90(1):11-21. doi: 10.1007/s00253-011-3128-3. Epub 2011 Feb 20.
• [9] Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.Am J Med Genet A. 2017 Apr;173(4):1102-1108. doi: 10.1002/ajmg.a.38116.
• [10] Expression of IARS2 gene in colon cancer and effect of its knockdown on biological behavior of RKO cells.Int J Clin Exp Pathol. 2015 Oct 1;8(10):12151-9. eCollection 2015.
• [11] Knockdown of IARS2 suppressed growth of gastric cancer cells by regulating the phosphorylation of cell cycle-related proteins.Mol Cell Biochem. 2018 Jun;443(1-2):93-100. doi: 10.1007/s11010-017-3213-8. Epub 2017 Oct 25.
• [12] 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.
• [13] Alterations of repeated sequences in 5' upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome.Oncogene. 2001 Aug 23;20(37):5215-8. doi: 10.1038/sj.onc.1204578.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] 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.
• [18] 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.
• [19] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [20] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.