Details of Drug Off-Target (DOT)

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

• DOT Name: Methionine--tRNA ligase, mitochondrial (MARS2)
• Synonyms: EC 6.1.1.10; Methionyl-tRNA synthetase 2; Mitochondrial methionyl-tRNA synthetase; MtMetRS
• Gene Name: MARS2
• Related Disease:
  Mitochondrial disease
  Spastic ataxia 3
  Combined oxidative phosphorylation defect type 25
• UniProt ID: SYMM_HUMAN
• EC Number: 6.1.1.10
• Pfam ID: PF19303 ; PF09334
• Sequence:
  MLRTSVLRLLGRTGASRLSLLEDFGPRYYSSGSLSAGDDACDVRAYFTTPIFYVNAAPHI
  GHLYSALLADALCRHRRLRGPSTAATRFSTGTDEHGLKIQQAAATAGLAPTELCDRVSEQ
  FQQLFQEAGISCTDFIRTTEARHRVAVQHFWGVLKSRGLLYKGVYEGWYCASDECFLPEA
  KVTQQPGPSGDSFPVSLESGHPVSWTKEENYIFRLSQFRKPLQRWLRGNPQAITPEPFHH
  VVLQWLDEELPDLSVSRRSSHLHWGIPVPGDDSQTIYVWLDALVNYLTVIGYPNAEFKSW
  WPATSHIIGKDILKFHAIYWPAFLLGAGMSPPQRICVHSHWTVCGQKMSKSLGNVVDPRT
  CLNRYTVDGFRYFLLRQGVPNWDCDYYDEKVVKLLNSELADALGGLLNRCTAKRINPSET
  YPAFCTTCFPSEPGLVGPSVRAQAEDYALVSAVATLPKQVADHYDNFRIYKALEAVSSCV
  RQTNGFVQRHAPWKLNWESPVDAPWLGTVLHVALECLRVFGTLLQPVTPSLADKLLSRLG
  VSASERSLGELYFLPRFYGHPCPFEGRRLGPETGLLFPRLDQSRTWLVKAHRT
• KEGG Pathway:
  Selenocompound metabolism (hsa00450)
  Aminoacyl-tR. biosynthesis (hsa00970)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Spastic ataxia 3	DISLCZN8	Moderate	Autosomal recessive	[2]
Combined oxidative phosphorylation defect type 25	DISUGLZ8	Supportive	Autosomal recessive	[3]

12 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, mitochondrial (MARS2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Methionine--tRNA ligase, mitochondrial (MARS2).	[16]

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 decreases the methylation of Methionine--tRNA ligase, mitochondrial (MARS2).	[14]

References

• [1] 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.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss. Hum Mutat. 2015 Jun;36(6):587-92. doi: 10.1002/humu.22781. Epub 2015 Apr 8.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.