Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW8D813)

• DOT Name: Alanine--tRNA ligase, cytoplasmic (AARS1)
• Synonyms: EC 6.1.1.7; Alanyl-tRNA synthetase; AlaRS; Renal carcinoma antigen NY-REN-42
• Gene Name: AARS1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Charcot-Marie-Tooth disease axonal type 2N
  Undetermined early-onset epileptic encephalopathy
  Cerebellar ataxia
  Charcot-Marie-Tooth disease type 2
  Developmental and epileptic encephalopathy, 29
  Idiopathic inflammatory myopathy
  Leukoencephalopathy, hereditary diffuse, with spheroids
  Myositis disease
  Nervous system disease
  Peripheral neuropathy
  West syndrome
  Charcot marie tooth disease
  Isolated congenital microcephaly
  Cardiomyopathy
  Trichothiodystrophy 8, nonphotosensitive
• UniProt ID: SYAC_HUMAN
• PDB ID: 4XEM; 4XEO; 5KNN; 5T5S; 5T76; 5V59
• EC Number: 6.1.1.7
• Pfam ID: PF02272 ; PF01411 ; PF07973
• Sequence:
  MDSTLTASEIRQRFIDFFKRNEHTYVHSSATIPLDDPTLLFANAGMNQFKPIFLNTIDPS
  HPMAKLSRAANTQKCIRAGGKHNDLDDVGKDVYHHTFFEMLGSWSFGDYFKELACKMALE
  LLTQEFGIPIERLYVTYFGGDEAAGLEADLECKQIWQNLGLDDTKILPGNMKDNFWEMGD
  TGPCGPCSEIHYDRIGGRDAAHLVNQDDPNVLEIWNLVFIQYNREADGILKPLPKKSIDT
  GMGLERLVSVLQNKMSNYDTDLFVPYFEAIQKGTGARPYTGKVGAEDADGIDMAYRVLAD
  HARTITVALADGGRPDNTGRGYVLRRILRRAVRYAHEKLNASRGFFATLVDVVVQSLGDA
  FPELKKDPDMVKDIINEEEVQFLKTLSRGRRILDRKIQSLGDSKTIPGDTAWLLYDTYGF
  PVDLTGLIAEEKGLVVDMDGFEEERKLAQLKSQGKGAGGEDLIMLDIYAIEELRARGLEV
  TDDSPKYNYHLDSSGSYVFENTVATVMALRREKMFVEEVSTGQECGVVLDKTCFYAEQGG
  QIYDEGYLVKVDDSSEDKTEFTVKNAQVRGGYVLHIGTIYGDLKVGDQVWLFIDEPRRRP
  IMSNHTATHILNFALRSVLGEADQKGSLVAPDRLRFDFTAKGAMSTQQIKKAEEIANEMI
  EAAKAVYTQDCPLAAAKAIQGLRAVFDETYPDPVRVVSIGVPVSELLDDPSGPAGSLTSV
  EFCGGTHLRNSSHAGAFVIVTEEAIAKGIRRIVAVTGAEAQKALRKAESLKKCLSVMEAK
  VKAQTAPNKDVQREIADLGEALATAVIPQWQKDELRETLKSLKKVMDDLDRASKADVQKR
  VLEKTKQFIDSNPNQPLVILEMESGASAKALNEALKLFKMHSPQTSAMLFTVDNEAGKIT
  CLCQVPQNAANRGLKASEWVQQVSGLMDGKGGGKDVSAQATGKNVGCLQEALQLATSFAQ
  LRLGDVKN
• Function: Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

17 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]
Charcot-Marie-Tooth disease axonal type 2N	DIS8BG8Q	Definitive	Autosomal dominant	[2]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Definitive	Autosomal recessive	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	CausalMutation	[5]
Developmental and epileptic encephalopathy, 29	DISX8GVU	Strong	Autosomal recessive	[6]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[7]
Leukoencephalopathy, hereditary diffuse, with spheroids	DIS4DF8A	Strong	Genetic Variation	[8]
Myositis disease	DISCIXF0	Strong	Biomarker	[9]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[3]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[10]
West syndrome	DISLIAU9	Strong	Biomarker	[11]
Charcot marie tooth disease	DIS3BT2L	moderate	Genetic Variation	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[3]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[12]
Trichothiodystrophy 8, nonphotosensitive	DIS30UOW	Limited	Unknown	[13]

27 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 Alanine--tRNA ligase, cytoplasmic (AARS1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[22]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[23]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[24]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[18]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[18]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[25]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[34]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[36]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[37]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Alanine--tRNA ligase, cytoplasmic (AARS1).	[38]

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 Alanine--tRNA ligase, cytoplasmic (AARS1).	[30]

1 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 increases the phosphorylation of Alanine--tRNA ligase, cytoplasmic (AARS1).	[33]

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] 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.
• [3] Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum Mutat. 2017 Oct;38(10):1348-1354. doi: 10.1002/humu.23250. Epub 2017 Jun 23.
• [4] Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.Nature. 2006 Sep 7;443(7107):50-5. doi: 10.1038/nature05096. Epub 2006 Aug 13.
• [5] Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.Hum Mol Genet. 2018 Dec 1;27(23):4036-4050. doi: 10.1093/hmg/ddy290.
• [6] Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am J Hum Genet. 2015 Apr 2;96(4):675-81. doi: 10.1016/j.ajhg.2015.02.012. Epub 2015 Mar 26.
• [7] Comprehensive insight into human aminoacyl-tRNA synthetases as autoantigens in idiopathic inflammatory myopathies.Crit Rev Immunol. 2007;27(6):559-72. doi: 10.1615/critrevimmunol.v27.i6.60.
• [8] An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids.Acta Neuropathol Commun. 2019 Nov 27;7(1):188. doi: 10.1186/s40478-019-0843-y.
• [9] Pulmonary Pathologic Manifestations of Anti-Alanyl-tRNA Synthetase (Anti-PL-12)-Related Inflammatory Myopathy.Arch Pathol Lab Med. 2018 Feb;142(2):191-197. doi: 10.5858/arpa.2017-0010-OA. Epub 2017 Oct 2.
• [10] A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).Hum Mutat. 2012 Jan;33(1):244-53. doi: 10.1002/humu.21635. Epub 2011 Nov 9.
• [11] Genotype-phenotype correlation on 45 individuals with West syndrome.Eur J Paediatr Neurol. 2020 Mar;25:134-138. doi: 10.1016/j.ejpn.2019.11.010. Epub 2019 Nov 26.
• [12] Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy.Hum Mol Genet. 2019 Jan 15;28(2):258-268. doi: 10.1093/hmg/ddy294.
• [13] Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy. Hum Mol Genet. 2021 Aug 28;30(18):1711-1720. doi: 10.1093/hmg/ddab123.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] 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.
• [20] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [23] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [24] 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.
• [25] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [26] 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.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [29] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [30] 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.
• [31] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [32] 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.
• [33] 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.
• [34] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [35] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [36] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [37] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [38] 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.