Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHPZ6JN)

• DOT Name: Arginine--tRNA ligase, cytoplasmic (RARS1)
• Synonyms: EC 6.1.1.19; Arginyl-tRNA synthetase; ArgRS
• Gene Name: RARS1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Childhood myelodysplastic syndrome
  Chronic myelomonocytic leukemia
  Essential thrombocythemia
  Head and neck cancer
  Head and neck carcinoma
  Hypomyelinating leukodystrophy 9
  Intellectual disability
  Leukodystrophy
  Myelodysplastic syndrome
  Myelodysplastic/myeloproliferative neoplasm
  Myelofibrosis
  Nasopharyngeal carcinoma
  Neoplasm
  Partial trisomy of the long arm of chromosome 5
  Pelizeaus-Merzbacher spectrum disorder
  Primary myelofibrosis
  Small lymphocytic lymphoma
  Thrombocytosis disease
  Anemia
  Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
  Pathologic nystagmus
  Chronic myelomonocytic leukaemia
  Acute myelogenous leukaemia
  leukaemia
  Leukemia
  Myeloproliferative neoplasm
  Neurodevelopmental disorder
  Pontocerebellar hypoplasia type 6
• UniProt ID: SYRC_HUMAN
• PDB ID: 4Q2T; 4Q2X; 4Q2Y; 4R3Z; 4ZAJ
• EC Number: 6.1.1.19
• Pfam ID: PF03485 ; PF05746 ; PF00750
• Sequence:
  MDVLVSECSARLLQQEEEIKSLTAEIDRLKNCGCLGASPNLEQLQEENLKLKYRLNILRK
  SLQAERNKPTKNMINIISRLQEVFGHAIKAAYPDLENPPLLVTPSQQAKFGDYQCNSAMG
  ISQMLKTKEQKVNPREIAENITKHLPDNECIEKVEIAGPGFINVHLRKDFVSEQLTSLLV
  NGVQLPALGENKKVIVDFSSPNIAKEMHVGHLRSTIIGESISRLFEFAGYDVLRLNHVGD
  WGTQFGMLIAHLQDKFPDYLTVSPPIGDLQVFYKESKKRFDTEEEFKKRAYQCVVLLQGK
  NPDITKAWKLICDVSRQELNKIYDALDVSLIERGESFYQDRMNDIVKEFEDRGFVQVDDG
  RKIVFVPGCSIPLTIVKSDGGYTYDTSDLAAIKQRLFEEKADMIIYVVDNGQSVHFQTIF
  AAAQMIGWYDPKVTRVFHAGFGVVLGEDKKKFKTRSGETVRLMDLLGEGLKRSMDKLKEK
  ERDKVLTAEELNAAQTSVAYGCIKYADLSHNRLNDYIFSFDKMLDDRGNTAAYLLYAFTR
  IRSIARLANIDEEMLQKAARETKILLDHEKEWKLGRCILRFPEILQKILDDLFLHTLCDY
  IYELATAFTEFYDSCYCVEKDRQTGKILKVNMWRMLLCEAVAAVMAKGFDILGIKPVQRM
• Function: Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis. Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway:
  Cytosolic tRNA aminoacylation (R-HSA-379716)
  Selenoamino acid metabolism (R-HSA-2408522)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[3]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Biomarker	[4]
Essential thrombocythemia	DISWWK11	Strong	Genetic Variation	[3]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[2]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[2]
Hypomyelinating leukodystrophy 9	DIS3MJVL	Strong	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Leukodystrophy	DISVY1TT	Strong	Biomarker	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Genetic Variation	[9]
Myelofibrosis	DISIMP21	Strong	Biomarker	[10]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[11]
Partial trisomy of the long arm of chromosome 5	DISFHG81	Strong	Biomarker	[12]
Pelizeaus-Merzbacher spectrum disorder	DIS1ODJO	Strong	Biomarker	[13]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[10]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[14]
Thrombocytosis disease	DISNG0P4	Strong	Biomarker	[15]
Anemia	DISTVL0C	moderate	Biomarker	[10]
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	DISPBAUD	moderate	Genetic Variation	[16]
Pathologic nystagmus	DIS1QSPO	moderate	Genetic Variation	[7]
Chronic myelomonocytic leukaemia	DISDN5P7	Disputed	Genetic Variation	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[17]
leukaemia	DISS7D1V	Limited	Biomarker	[17]
Leukemia	DISNAKFL	Limited	Biomarker	[17]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Biomarker	[8]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[16]
Pontocerebellar hypoplasia type 6	DIS9BKLQ	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[22]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[26]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Arginine--tRNA ligase, cytoplasmic (RARS1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Arginine--tRNA ligase, cytoplasmic (RARS1).	[24]

References

• [1] Potentially functional polymorphisms in aminoacyl-tRNA synthetases genes are associated with breast cancer risk in a Chinese population.Mol Carcinog. 2015 Jul;54(7):577-83. doi: 10.1002/mc.22128. Epub 2014 Feb 9.
• [2] The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma. Clin Cancer Res. 2018 Feb 1;24(3):659-673.
• [3] Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category?.Br J Haematol. 2009 Mar;144(6):809-17. doi: 10.1111/j.1365-2141.2008.07526.x. Epub 2008 Dec 11.
• [4] The incidence of myelodysplastic syndromes in Western Greece is increasing.Ann Hematol. 2013 Jul;92(7):877-87. doi: 10.1007/s00277-013-1712-6. Epub 2013 Apr 10.
• [5] Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. doi: 10.1038/ng.425. Epub 2009 Aug 16.
• [6] Mutations in RARS cause hypomyelination. Ann Neurol. 2014 Jul;76(1):134-9. doi: 10.1002/ana.24167. Epub 2014 May 16.
• [7] RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.Ann Clin Transl Neurol. 2020 Jan;7(1):83-93. doi: 10.1002/acn3.50960. Epub 2019 Dec 8.
• [8] Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing.Am J Hematol. 2016 May;91(5):492-8. doi: 10.1002/ajh.24332. Epub 2016 Apr 4.
• [9] Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable.Int J Hematol. 2015 Mar;101(3):229-42. doi: 10.1007/s12185-014-1670-3. Epub 2014 Sep 12.
• [10] The role of JAK2 mutations in RARS and other MDS.Hematology Am Soc Hematol Educ Program. 2008:52-9. doi: 10.1182/asheducation-2008.1.52.
• [11] Aberrant methylation of tumor suppressor genes in patients with refractory anemia with ring sideroblasts.Leuk Res. 2011 Apr;35(4):479-83. doi: 10.1016/j.leukres.2010.08.012. Epub 2010 Sep 22.
• [12] Presence of peripheral blasts in refractory anemia and refractory cytopenia with multilineage dysplasia predicts an unfavourable outcome.Leuk Res. 2008 Jan;32(1):33-7. doi: 10.1016/j.leukres.2007.02.021. Epub 2007 Apr 6.
• [13] Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease.Eur J Hum Genet. 2017 Oct;25(10):1134-1141. doi: 10.1038/ejhg.2017.119. Epub 2017 Jul 26.
• [14] miR-15a and miR-16-1 down-regulation in pituitary adenomas.J Cell Physiol. 2005 Jul;204(1):280-5. doi: 10.1002/jcp.20282.
• [15] Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis.Blood. 2010 Jul 15;116(2):180-2. doi: 10.1182/blood-2010-01-263087. Epub 2010 Mar 1.
• [16] Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations.J Biol Chem. 2018 Aug 31;293(35):13604-13615. doi: 10.1074/jbc.RA118.003400. Epub 2018 Jul 13.
• [17] A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia.Haematologica. 2007 Jun;92(6):744-52. doi: 10.3324/haematol.10869.
• [18] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [19] 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.
• [20] 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.
• [21] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [22] 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.
• [23] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [24] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [27] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.