Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLJ6MHJ)

• DOT Name: Methionine--tRNA ligase, cytoplasmic (MARS1)
• Synonyms: EC 6.1.1.10; Methionyl-tRNA synthetase; MetRS
• Gene Name: MARS1
• Related Disease:
  Charcot-Marie-Tooth disease axonal type 2U
  Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
  Autosomal recessive spastic paraplegia type 70
  Charcot marie tooth disease
  Spastic paraplegia 70, autosomal recessive
  Trichothiodystrophy 9, nonphotosensitive
• UniProt ID: SYMC_HUMAN
• PDB ID: 2DJV; 4BL7; 4BVX; 4BVY; 5GL7; 5GOY; 5Y6L
• EC Number: 6.1.1.10
• Pfam ID: PF19303 ; PF00043 ; PF18485 ; PF09334 ; PF00458
• Sequence:
  MRLFVSDGVPGCLPVLAAAGRARGRAEVLISTVGPEDCVVPFLTRPKVPVLQLDSGNYLF
  STSAICRYFFLLSGWEQDDLTNQWLEWEATELQPALSAALYYLVVQGKKGEDVLGSVRRA
  LTHIDHSLSRQNCPFLAGETESLADIVLWGALYPLLQDPAYLPEELSALHSWFQTLSTQE
  PCQRAAETVLKQQGVLALRPYLQKQPQPSPAEGRAVTNEPEEEELATLSEEEIAMAVTAW
  EKGLESLPPLRPQQNPVLPVAGERNVLITSALPYVNNVPHLGNIIGCVLSADVFARYSRL
  RQWNTLYLCGTDEYGTATETKALEEGLTPQEICDKYHIIHADIYRWFNISFDIFGRTTTP
  QQTKITQDIFQQLLKRGFVLQDTVEQLRCEHCARFLADRFVEGVCPFCGYEEARGDQCDK
  CGKLINAVELKKPQCKVCRSCPVVQSSQHLFLDLPKLEKRLEEWLGRTLPGSDWTPNAQF
  ITRSWLRDGLKPRCITRDLKWGTPVPLEGFEDKVFYVWFDATIGYLSITANYTDQWERWW
  KNPEQVDLYQFMAKDNVPFHSLVFPCSALGAEDNYTLVSHLIATEYLNYEDGKFSKSRGV
  GVFGDMAQDTGIPADIWRFYLLYIRPEGQDSAFSWTDLLLKNNSELLNNLGNFINRAGMF
  VSKFFGGYVPEMVLTPDDQRLLAHVTLELQHYHQLLEKVRIRDALRSILTISRHGNQYIQ
  VNEPWKRIKGSEADRQRAGTVTGLAVNIAALLSVMLQPYMPTVSATIQAQLQLPPPACSI
  LLTNFLCTLPAGHQIGTVSPLFQKLENDQIESLRQRFGGGQAKTSPKPAVVETVTTAKPQ
  QIQALMDEVTKQGNIVRELKAQKADKNEVAAEVAKLLDLKKQLAVAEGKPPEAPKGKKKK
• 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. Plays a role in the synthesis of ribosomal RNA in the nucleolus.
• KEGG Pathway:
  Selenocompound metabolism (hsa00450)
  Aminoacyl-tR. biosynthesis (hsa00970)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Cytosolic tRNA aminoacylation (R-HSA-379716)
  Selenoamino acid metabolism (R-HSA-2408522)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease axonal type 2U	DISRCJLT	Strong	Autosomal dominant	[1]
Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency	DIS9EFIT	Strong	Autosomal recessive	[2]
Autosomal recessive spastic paraplegia type 70	DIS8SGWX	Supportive	Autosomal recessive	[3]
Charcot marie tooth disease	DIS3BT2L	Limited	Autosomal dominant	[4]
Spastic paraplegia 70, autosomal recessive	DISHV3HM	Limited	Unknown	[3]
Trichothiodystrophy 9, nonphotosensitive	DISQ0Z8H	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[15]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[20]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Methionine--tRNA ligase, cytoplasmic (MARS1).	[21]

References

• [1] Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):1247-9. doi: 10.1136/jnnp-2013-305049. Epub 2013 Jun 1.
• [2] Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med Genet. 2013 Oct 8;14:106. doi: 10.1186/1471-2350-14-106.
• [3] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [4] 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.
• [5] 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.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [21] 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.