Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRQC5ER)

• DOT Name: tRNA (METTL1)
• Synonyms: guanine-N(7)-)-methyltransferase (EC 2.1.1.33; Methyltransferase-like protein 1; mRNA (guanine-N(7)-)-methyltransferase; EC 2.1.1.-; miRNA (guanine-N(7)-)-methyltransferase; EC 2.1.1.-; tRNA (guanine(46)-N(7))-methyltransferase; tRNA(m7G46)-methyltransferase
• Gene Name: METTL1
• Related Disease:
  Hepatocellular carcinoma
  Multiple sclerosis
  Neoplasm
• UniProt ID: TRMB_HUMAN
• PDB ID: 3CKK; 7OGJ; 7PL1; 7U20; 8CTH; 8CTI; 8D58; 8D59; 8D5B; 8D9K; 8D9L; 8EG0; 8H0N
• EC Number: 2.1.1.-; 2.1.1.33
• Pfam ID: PF02390
• Sequence:
  MAAETRNVAGAEAPPPQKRYYRQRAHSNPMADHTLRYPVKPEEMDWSELYPEFFAPLTQN
  QSHDDPKDKKEKRAQAQVEFADIGCGYGGLLVELSPLFPDTLILGLEIRVKVSDYVQDRI
  RALRAAPAGGFQNIACLRSNAMKHLPNFFYKGQLTKMFFLFPDPHFKRTKHKWRIISPTL
  LAEYAYVLRVGGLVYTITDVLELHDWMCTHFEEHPLFERVPLEDLSEDPVVGHLGTSTEE
  GKKVLRNGGKNFPAIFRRIQDPVLQAVTSQTSLPGH
• Function: Catalytic component of METTL1-WDR4 methyltransferase complex that mediates the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop. M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay. Also acts as a methyltransferase for a subset of internal N(7)-methylguanine in mRNAs. Internal N(7)-methylguanine methylation of mRNAs in response to stress promotes their relocalization to stress granules, thereby suppressing their translation. Also methylates a specific subset of miRNAs, such as let-7. N(7)-methylguanine methylation of let-7 miRNA promotes let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). Acts as a regulator of embryonic stem cell self-renewal and differentiation.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (METTL1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA (METTL1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA (METTL1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA (METTL1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of tRNA (METTL1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of tRNA (METTL1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of tRNA (METTL1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of tRNA (METTL1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA (METTL1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA (METTL1).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of tRNA (METTL1).	[14]

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 tRNA (METTL1).	[13]

References

• [1] METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.J Mol Med (Berl). 2019 Nov;97(11):1535-1545. doi: 10.1007/s00109-019-01830-9. Epub 2019 Aug 28.
• [2] Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis.J Neurol. 2019 Nov;266(11):2699-2709. doi: 10.1007/s00415-019-09476-w. Epub 2019 Jul 18.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.