Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOUZF6O)

• DOT Name: Cysteine--tRNA ligase, cytoplasmic (CARS1)
• Synonyms: EC 6.1.1.16; Cysteinyl-tRNA synthetase; CysRS
• Gene Name: CARS1
• Related Disease:
  Alcohol dependence
  Anaplastic large cell lymphoma
  Autism
  Isolated congenital microcephaly
  Mitochondrial DNA depletion syndrome 4a
  Cornelia de Lange syndrome
  Diabetic kidney disease
  Nephropathy
  Stroke
  Type-1/2 diabetes
• UniProt ID: SYCC_HUMAN
• EC Number: 6.1.1.16
• Pfam ID: PF01406
• Sequence:
  MADSSGQQGKGRRVQPQWSPPAGTQPCRLHLYNSLTRNKEVFIPQDGKKVTWYCCGPTVY
  DASHMGHARSYISFDILRRVLKDYFKFDVFYCMNITDIDDKIIKRARQNHLFEQYREKRP
  EAAQLLEDVQAALKPFSVKLNETTDPDKKQMLERIQHAVQLATEPLEKAVQSRLTGEEVN
  SCVEVLLEEAKDLLSDWLDSTLGCDVTDNSIFSKLPKFWEGDFHRDMEALNVLPPDVLTR
  VSEYVPEIVNFVQKIVDNGYGYVSNGSVYFDTAKFASSEKHSYGKLVPEAVGDQKALQEG
  EGDLSISADRLSEKRSPNDFALWKASKPGEPSWPCPWGKGRPGWHIECSAMAGTLLGASM
  DIHGGGFDLRFPHHDNELAQSEAYFENDCWVRYFLHTGHLTIAGCKMSKSLKNFITIKDA
  LKKHSARQLRLAFLMHSWKDTLDYSSNTMESALQYEKFLNEFFLNVKDILRAPVDITGQF
  EKWGEEEAELNKNFYDKKTAIHKALCDNVDTRTVMEEMRALVSQCNLYMAARKAVRKRPN
  QALLENIALYLTHMLKIFGAVEEDSSLGFPVGGPGTSLSLEATVMPYLQVLSEFREGVRK
  IAREQKVPEILQLSDALRDNILPELGVRFEDHEGLPTVVKLVDRNTLLKEREEKRRVEEE
  KRKKKEEAARRKQEQEAAKLAKMKIPPSEMFLSETDKYSKFDENGLPTHDMEGKELSKGQ
  AKKLKKLFEAQEKLYKEYLQMAQNGSFQ
• Function: Catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway:
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Strong	Genetic Variation	[5]
Cornelia de Lange syndrome	DISEQSXO	moderate	Genetic Variation	[3]
Diabetic kidney disease	DISJMWEY	moderate	Biomarker	[6]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[7]
Stroke	DISX6UHX	moderate	Genetic Variation	[8]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[7]

29 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 Cysteine--tRNA ligase, cytoplasmic (CARS1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[19]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[20]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[21]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[13]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[22]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[13]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[13]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[22]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[30]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[31]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[32]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cysteine--tRNA ligase, cytoplasmic (CARS1).	[28]

References

• [1] Genome-wide association study of alcohol dependence implicates a region on chromosome 11.Alcohol Clin Exp Res. 2010 May;34(5):840-52. doi: 10.1111/j.1530-0277.2010.01156.x. Epub 2010 Mar 1.
• [2] Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.Genes Chromosomes Cancer. 2002 Aug;34(4):354-62. doi: 10.1002/gcc.10033.
• [3] Autism traits in children and adolescents with Cornelia de Lange syndrome.Am J Med Genet A. 2014 Jun;164A(6):1400-10. doi: 10.1002/ajmg.a.36573. Epub 2014 Apr 9.
• [4] Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.Am J Hum Genet. 2019 Mar 7;104(3):520-529. doi: 10.1016/j.ajhg.2019.01.006. Epub 2019 Feb 26.
• [5] Clinicopathologic Findings of CARS2 Mutation.Pediatr Neurol. 2018 Oct;87:65-69. doi: 10.1016/j.pediatrneurol.2018.06.009. Epub 2018 Jul 4.
• [6] Evaluation of associations between single nucleotide polymorphisms in the FRMD3 and CARS genes and diabetic nephropathy in a Kuwaiti population.Genet Mol Res. 2016 Jan 29;15(1). doi: 10.4238/gmr.15017619.
• [7] An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes.Kidney Int. 2011 Jul;80(1):105-11. doi: 10.1038/ki.2011.64. Epub 2011 Mar 16.
• [8] Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials.Neurol Sci. 2017 Oct;38(10):1761-1769. doi: 10.1007/s10072-017-3037-z. Epub 2017 Jul 13.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [14] 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.
• [15] Gene expression profile changes in NB4 cells induced by arsenic trioxide. Acta Pharmacol Sin. 2003 Jul;24(7):646-50.
• [16] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [17] 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.
• [18] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [21] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [22] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [23] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [26] 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.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [28] 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.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [31] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [32] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [33] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.