Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAYQ8ZF)

• DOT Name: tRNA (TRDMT1)
• Synonyms: cytosine(38)-C(5))-methyltransferase (EC 2.1.1.204; DNA (cytosine-5)-methyltransferase-like protein 2; Dnmt2; DNA methyltransferase homolog HsaIIP; DNA MTase homolog HsaIIP; M.HsaIIP; PuMet
• Gene Name: TRDMT1
• Related Disease:
  Lung cancer
  Lung carcinoma
  Small-cell lung cancer
  Cardiovascular disease
  Colorectal carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Metabolic disorder
  Myocardial infarction
  Neoplasm
  Neural tube defect
  Prostate neoplasm
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Advanced cancer
• UniProt ID: TRDMT_HUMAN
• PDB ID: 1G55
• EC Number: 2.1.1.204
• Pfam ID: PF00145
• Sequence:
  MEPLRVLELYSGVGGMHHALRESCIPAQVVAAIDVNTVANEVYKYNFPHTQLLAKTIEGI
  TLEEFDRLSFDMILMSPPCQPFTRIGRQGDMTDSRTNSFLHILDILPRLQKLPKYILLEN
  VKGFEVSSTRDLLIQTIENCGFQYQEFLLSPTSLGIPNSRLRYFLIAKLQSEPLPFQAPG
  QVLMEFPKIESVHPQKYAMDVENKIQEKNVEPNISFDGSIQCSGKDAILFKLETAEEIHR
  KNQQDSDLSVKMLKDFLEDDTDVNQYLLPPKSLLRYALLLDIVQPTCRRSVCFTKGYGSY
  IEGTGSVLQTAEDVQVENIYKSLTNLSQEEQITKLLILKLRYFTPKEIANLLGFPPEFGF
  PEKITVKQRYRLLGNSLNVHVVAKLIKILYE
• Function: Specifically methylates cytosine 38 in the anticodon loop of tRNA(Asp). Has higher activity on tRNA(Asp) modified with queuosine at position 34.
• Tissue Specificity: Ubiquitous. Higher expression in testis, ovary and thymus and at much lower levels in spleen, prostate, colon, small intestine, and peripheral blood leukocytes.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)
• BioCyc Pathway: MetaCyc:HS03011-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Genetic Variation	[1]
Lung carcinoma	DISTR26C	Definitive	Genetic Variation	[1]
Small-cell lung cancer	DISK3LZD	Definitive	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[5]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Neural tube defect	DIS5J95E	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[9]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[10]

9 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 tRNA (TRDMT1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (TRDMT1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA (TRDMT1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of tRNA (TRDMT1).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of tRNA (TRDMT1).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of tRNA (TRDMT1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA (TRDMT1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of tRNA (TRDMT1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of tRNA (TRDMT1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of tRNA (TRDMT1).	[19]

References

• [1] Prognostic significance of folate metabolism polymorphisms for lung cancer.Br J Cancer. 2007 Jul 16;97(2):247-52. doi: 10.1038/sj.bjc.6603830. Epub 2007 May 29.
• [2] Genetic modifiers of folate, vitamin B-12, and homocysteine status in a cross-sectional study of the Canadian population.Am J Clin Nutr. 2015 Jun;101(6):1295-304. doi: 10.3945/ajcn.115.107219. Epub 2015 May 6.
• [3] Risk-association of DNA methyltransferases polymorphisms with gastric cancer in the Southern Chinese population.Int J Mol Sci. 2012;13(7):8364-8378. doi: 10.3390/ijms13078364. Epub 2012 Jul 5.
• [4] Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis.Hepatology. 2001 Mar;33(3):561-8. doi: 10.1053/jhep.2001.22507.
• [5] Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs.Nat Cell Biol. 2018 May;20(5):535-540. doi: 10.1038/s41556-018-0087-2. Epub 2018 Apr 25.
• [6] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [7] Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to oxidative stress and DNA damage that is accompanied by changes in proliferation-related miRNA expression.Redox Biol. 2018 Apr;14:20-34. doi: 10.1016/j.redox.2017.08.012. Epub 2017 Aug 18.
• [8] Cytogenetic and expression profiles associated with transformation to androgen-resistant prostate cancer.Prostate. 2006 Feb 1;66(2):157-72. doi: 10.1002/pros.20328.
• [9] Association of DNMT1 and DNMT3B polymorphisms with breast cancer risk in Han Chinese women from South China.Genet Mol Res. 2012 Dec 17;11(4):4330-41. doi: 10.4238/2012.September.26.1.
• [10] Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties.Biochimie. 2015 May;112:66-72. doi: 10.1016/j.biochi.2015.02.022. Epub 2015 Mar 5.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] 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.
• [14] 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.
• [15] Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis. 2008 Nov;29(11):2175-81.
• [16] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [19] 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.
• [20] 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.