Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNE7W96)

• DOT Name: tRNA (FTSJ1)
• Synonyms: cytidine(32)/guanosine(34)-2'-O)-methyltransferase (EC 2.1.1.205; 2'-O-ribose RNA methyltransferase TRM7 homolog; Protein ftsJ homolog 1
• Gene Name: FTSJ1
• Related Disease:
  Hepatocellular carcinoma
  Intellectual disability, X-linked 9
  X-linked complex neurodevelopmental disorder
  Epilepsy
  Intellectual disability, X-linked 1
  Obesity
  Trichohepatoenteric syndrome
  X-linked intellectual disability
  Non-syndromic X-linked intellectual disability
  Hyperglycemia
  Streptococcal B infection
• UniProt ID: TRM7_HUMAN
• EC Number: 2.1.1.205
• Pfam ID: PF01728
• Sequence:
  MGRTSKDKRDVYYRLAKENGWRARSAFKLLQLDKEFQLFQGVTRAVDLCAAPGSWSQVLS
  QKIGGQGSGHVVAVDLQAMAPLPGVVQIQGDITQLSTAKEIIQHFKGCPADLVVCDGAPD
  VTGLHDVDEYMQAQLLLAALNIATHVLKPGGCFVAKIFRGRDVTLLYSQLQVFFSSVLCA
  KPRSSRNSSIEAFAVCQGYDPPEGFIPDLSKPLLDHSYDPDFNQLDGPTRIIVPFVTCGD
  LSSYDSDRSYPLDLEGGSEYKYTPPTQPPISPPYQEACTLKRKGQLAKEIRPQDCPISRV
  DTFPQPLAAPQCHTLLAPEMEDNEMSCSP
• Function: Methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs. Requisite for faithful cytoplasmic translation. Requires THADA for methylation of the nucleotide at position 32 of the anticodon loop of substrate tRNAs. Requires WDR6 for methylation of the nucleotide at position 34 of the anticodon loop of substrate tRNAs. Promotes translation efficiency of the UUU codon. Plays a role in neurogenesis. Required for expression of genes involved in neurogenesis, mitochondrial translation and energy generation, and lipid biosynthesis. Requisite for RNA-mediated gene silencing. May modify position 32 in tRNA(Arg(ACG)), tRNA(Arg(CCG)), tRNA(Arg(UCG)), tRNA(Cys(GCA)), tRNA(Cys(ACA)), tRNA(Gln(CUG)), tRNA(Gln(UUG)), tRNA(Gly(CCC)), tRNA(Leu(CAG))/tRNA(Leu(CAA)), tRNA(Leu(A/IAG)), tRNA(Leu(UAG)), tRNA(Phe(GAA)), tRNA(Pro(AGG))/tRNA(Pro(CGG))/tRNA(Pro(UGG)) and tRNA(Trp(CCA)), and position 34 in tRNA(Phe(GAA)), tRNA(Leu(CAA)), tRNA(Sec(UCA)), and tRNA(Trp(CCA)).
• Tissue Specificity: Found in fetal brain, lung, liver and kidney . Widely expressed in adult tissue; with high expression in heart and liver, lower expression in skeletal muscle, kidney, and pancreas and also lowly expressed in brain and lung . In the adult brain, expressed in amygdala, caudate nucleus, corpus callosum, hippocampus and thalamus .
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Intellectual disability, X-linked 9	DISWT4BP	Definitive	X-linked	[2]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[4]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[7]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[5]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[6]
Streptococcal B infection	DISN80QT	Limited	Biomarker	[8]

10 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 (FTSJ1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (FTSJ1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA (FTSJ1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA (FTSJ1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of tRNA (FTSJ1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA (FTSJ1).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of tRNA (FTSJ1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of tRNA (FTSJ1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA (FTSJ1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of tRNA (FTSJ1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of tRNA (FTSJ1).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of tRNA (FTSJ1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of tRNA (FTSJ1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of tRNA (FTSJ1).	[19]

References

• [1] Nucleoporin Nup155 is part of the p53 network in liver cancer.Nat Commun. 2019 May 14;10(1):2147. doi: 10.1038/s41467-019-10133-z.
• [2] Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental retardation: clinical and psychometric data and results of linkage analysis. Am J Med Genet. 1999 Jul 30;85(3):290-304.
• [3] 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.
• [4] Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature.Am J Med Genet A. 2015 Jan;167A(1):111-22. doi: 10.1002/ajmg.a.36807. Epub 2014 Nov 25.
• [5] A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):479-84. doi: 10.1002/ajmg.b.30638.
• [6] Evaluation of Bacillus subtilis SPB1 biosurfactant effects on hyperglycemia, angiotensin I-converting enzyme (ACE) activity and kidney function in rats fed on high-fat-high-fructose diet.Arch Physiol Biochem. 2017 May;123(2):112-120. doi: 10.1080/13813455.2016.1261902. Epub 2016 Dec 25.
• [7] Positive association of the FTSJ1 gene polymorphisms with nonsyndromic X-linked mental retardation in young Chinese male subjects.J Hum Genet. 2008;53(7):592-597. doi: 10.1007/s10038-008-0287-x. Epub 2008 Apr 10.
• [8] Subtractive hybridization identifies a novel predicted protein mediating epithelial cell invasion by virulent serotype III group B Streptococcus agalactiae.Infect Immun. 2003 Dec;71(12):6857-63. doi: 10.1128/IAI.71.12.6857-6863.2003.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.