Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0WGC2T)

• DOT Name: Aspartate--tRNA ligase, cytoplasmic (DARS1)
• Synonyms: EC 6.1.1.12; Aspartyl-tRNA synthetase; AspRS; Cell proliferation-inducing gene 40 protein
• Gene Name: DARS1
• Related Disease:
  Hypomyelination with brain stem and spinal cord involvement and leg spasticity
  Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
  Non-insulin dependent diabetes
  Tuberculosis
  Ventricular septal defect
  Pontocerebellar hypoplasia type 6
  Nervous system disease
  Leukodystrophy
  Neurodevelopmental disorder
  Systemic lupus erythematosus
• UniProt ID: SYDC_HUMAN
• PDB ID: 4J15; 5Y6L; 6IY6
• EC Number: 6.1.1.12
• Pfam ID: PF00152 ; PF01336
• Sequence:
  MPSASASRKSQEKPREIMDAAEDYAKERYGISSMIQSQEKPDRVLVRVRDLTIQKADEVV
  WVRARVHTSRAKGKQCFLVLRQQQFNVQALVAVGDHASKQMVKFAANINKESIVDVEGVV
  RKVNQKIGSCTQQDVELHVQKIYVISLAEPRLPLQLDDAVRPEAEGEEEGRATVNQDTRL
  DNRVIDLRTSTSQAVFRLQSGICHLFRETLINKGFVEIQTPKIISAASEGGANVFTVSYF
  KNNAYLAQSPQLYKQMCICADFEKVFSIGPVFRAEDSNTHRHLTEFVGLDIEMAFNYHYH
  EVMEEIADTMVQIFKGLQERFQTEIQTVNKQFPCEPFKFLEPTLRLEYCEALAMLREAGV
  EMGDEDDLSTPNEKLLGHLVKEKYDTDFYILDKYPLAVRPFYTMPDPRNPKQSNSYDMFM
  RGEEILSGAQRIHDPQLLTERALHHGIDLEKIKAYIDSFRFGAPPHAGGGIGLERVTMLF
  LGLHNVRQTSMFPRDPKRLTP
• Function: Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
• Tissue Specificity: Expression in the developing and adult brain shows similar patterns. Highly expressed in the ventricular and subventricular zones, including hippocampal subfields, the midlateral temporal cortex and the frontal polar cortex. The cerebellum, cerebral cortex, hippocampus, and lateral ventricle show preferential neuronal expression. Expression in the peripheral neurons is evident in the colon.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypomyelination with brain stem and spinal cord involvement and leg spasticity	DIS2QDFZ	Definitive	Autosomal recessive	[1]
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	DISPBAUD	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[4]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[5]
Pontocerebellar hypoplasia type 6	DIS9BKLQ	moderate	Altered Expression	[2]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[6]
Leukodystrophy	DISVY1TT	Limited	Genetic Variation	[7]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[2]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[8]

16 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 Aspartate--tRNA ligase, cytoplasmic (DARS1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Aspartate--tRNA ligase, cytoplasmic (DARS1).	[22]

References

• [1] Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet. 2013 May 2;92(5):774-80. doi: 10.1016/j.ajhg.2013.04.006.
• [2] 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.
• [3] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [4] Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach.Sci Rep. 2018 Aug 23;8(1):12664. doi: 10.1038/s41598-018-31157-3.
• [5] Association of DARS gene polymorphisms with the risk of isolated ventricular septal defects in the Chinese Han population.Ital J Pediatr. 2016 Nov 21;42(1):102. doi: 10.1186/s13052-016-0311-2.
• [6] Atlas of human diseases influenced by genetic variants with extreme allele frequency differences.Hum Genet. 2017 Jan;136(1):39-54. doi: 10.1007/s00439-016-1734-y. Epub 2016 Oct 3.
• [7] Expression Pattern of the Aspartyl-tRNA Synthetase DARS in the Human Brain.Front Mol Neurosci. 2018 Mar 20;11:81. doi: 10.3389/fnmol.2018.00081. eCollection 2018.
• [8] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [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] 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.
• [14] Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res. 2009 Dec;89(6):995-1002. doi: 10.1016/j.exer.2009.08.011. Epub 2009 Sep 1.
• [15] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] 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.
• [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] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [19] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] 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.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.