Details of Drug Off-Target (DOT)

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

• DOT Name: Multifunctional methyltransferase subunit TRM112-like protein (TRMT112)
• Synonyms: tRNA methyltransferase 112 homolog
• Gene Name: TRMT112
• UniProt ID: TR112_HUMAN
• PDB ID: 6G4W; 6H1D; 6H1E; 6H2U; 6H2V; 6K0X; 6KHS; 6KMR; 6KMS; 6PED; 7WTS; 7WTT; 7WTU; 7WTV; 7WTW
• Pfam ID: PF03966
• Sequence:
  MKLLTHNLLSSHVRGVGSRGFPLRLQATEVRICPVEFNPNFVARMIPKVEWSAFLEAADN
  LRLIQVPKGPVEGYEENEEFLRTMHHLLLEVEVIEGTLQCPESGRMFPISRGIPNMLLSE
  EETES
• Function: Acts as an activator of both rRNA/tRNA and protein methyltransferases. Together with methyltransferase BUD23, methylates the N(7) position of a guanine in 18S rRNA. The heterodimer with N6AMT1/HEMK2 catalyzes N5-methylation of ETF1 on 'Gln-185', using S-adenosyl L-methionine as methyl donor. The heterodimer with N6AMT1/HEMK2 also monomethylates 'Lys-12' of histone H4 (H4K12me1). The heterodimer with ALKBH8 catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA species. Together with methyltransferase THUMPD3, catalyzes the formation of N(2)-methylguanosine at position 6 in a broad range of tRNA substrates and at position 7 of tRNA(Trp). Involved in the pre-rRNA processing steps leading to small-subunit rRNA production. Together with methyltransferase METTL5, specifically methylates the 6th position of adenine in position 1832 of 18S rRNA.
• Reactome Pathway:
  tRNA modification in the nucleus and cytosol (R-HSA-6782315)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Eukaryotic Translation Termination (R-HSA-72764)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:ENSG00000173113-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Multifunctional methyltransferase subunit TRM112-like protein (TRMT112) affects the response to substance of Acetaminophen.	[13]

11 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 Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[12]

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 Multifunctional methyltransferase subunit TRM112-like protein (TRMT112).	[10]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] 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.
• [11] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [12] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [13] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.