Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNTM9D1)

• DOT Name: Cytoplasmic tRNA 2-thiolation protein 1 (CTU1)
• Synonyms: EC 2.7.7.-; ATP-binding domain-containing protein 3; Cancer-associated gene protein; Cytoplasmic tRNA adenylyltransferase 1
• Gene Name: CTU1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal adenoma
  Neoplasm
  Carcinoma
  Colorectal neoplasm
  Gynecologic cancer
• UniProt ID: CTU1_HUMAN
• EC Number: 2.7.7.-
• Pfam ID: PF01171 ; PF16503
• Sequence:
  MPAPPCASCHAARAALRRPLSGQALCGACFCAAFEAEVLHTVLAGRLLPPGAVVAVGASG
  GKDSTVLAHVLRALAPRLGISLQLVAVDEGIGGYRDAALAAVRRQAARWELPLTVVAYED
  LFGGWTMDAVARSTAGSGRSRSCCTFCGVLRRRALEEGARRVGATHIVTGHNADDMAETV
  LMNFLRGDAGRLARGGGLGSPGEGGALPRCRPLQFASQKEVVLYAHFRRLDYFSEECVYA
  PEAFRGHARDLLKRLEAARPSAVLDLVHSAERLALAPAARPPRPGACSRCGALASRALCQ
  ACALLDGLNRGRPRLAIGKGRRGLDEEATPGTPGDPARPPASKAVPTF
• Function: Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of tRNA(Lys), tRNA(Glu) and tRNA(Gln). Directly binds tRNAs and probably acts by catalyzing adenylation of tRNAs, an intermediate required for 2-thiolation. It is unclear whether it acts as a sulfurtransferase that transfers sulfur from thiocarboxylated URM1 onto the uridine of tRNAs at wobble position.
• KEGG Pathway: Sulfur relay system (hsa04122)
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)
• BioCyc Pathway: MetaCyc:ENSG00000142544-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[6]
Colorectal neoplasm	DISR1UCN	Limited	Biomarker	[7]
Gynecologic cancer	DIST2NIJ	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytoplasmic tRNA 2-thiolation protein 1 (CTU1).	[14]

References

• [1] Identification, characterization and application of a new peptide against anterior gradient homolog 2 (AGR2). Oncotarget. 2018 Jun 8;9(44):27363-27379.
• [2] Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?.Acta Oncol. 2019;58(sup1):S42-S48. doi: 10.1080/0284186X.2018.1540885. Epub 2018 Dec 7.
• [3] Modulation of interaction of mutant TP53 and wild type BRCA1 by alkaloids: a computational approach towards targeting protein-protein interaction as a futuristic therapeutic intervention strategy for breast cancer impediment.J Biomol Struct Dyn. 2018 Oct;36(13):3376-3387. doi: 10.1080/07391102.2017.1388286. Epub 2017 Oct 23.
• [4] Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.J Exp Med. 2016 Oct 17;213(11):2503-2523. doi: 10.1084/jem.20160397. Epub 2016 Oct 10.
• [5] Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor.Cell. 2015 Jan 29;160(3):489-502. doi: 10.1016/j.cell.2015.01.001. Epub 2015 Jan 22.
• [6] Emerging role of microRNAs in modulating endothelin-1 expression in gastric cancer.Oncol Rep. 2015 Jan;33(1):485-93. doi: 10.3892/or.2014.3598. Epub 2014 Nov 11.
• [7] Expression pattern of breast-cancer-associated protein pS2/BCEI in colorectal tumors.Int J Cancer. 1994 Jan 2;56(1):52-5. doi: 10.1002/ijc.2910560110.
• [8] JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations.Sci Rep. 2013 Oct 24;3:3042. doi: 10.1038/srep03042.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.