Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC33MCV)

• DOT Name: Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1)
• Synonyms: EC 2.4.2.64; Guanine insertion enzyme; tRNA-guanine transglycosylase
• Gene Name: QTRT1
• Related Disease:
  Bacillary dysentery
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colorectal carcinoma
  Essential thrombocythemia
  Gestational trophoblastic neoplasia
  Hepatocellular carcinoma
  IgA nephropathy
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Multiple sclerosis
  Mycosis fungoides
  Myotonia fluctuans
  Neoplasm
  Pancreatitis
  Split hand-foot malformation
  Psoriasis
• UniProt ID: TGT_HUMAN
• PDB ID: 6H42; 6H45; 7NQ4
• EC Number: 2.4.2.64
• Pfam ID: PF01702
• Sequence:
  MAGAATQASLESAPRIMRLVAECSRSRARAGELWLPHGTVATPVFMPVGTQATMKGITTE
  QLDALGCRICLGNTYHLGLRPGPELIQKANGLHGFMNWPHNLLTDSGGFQMVSLVSLSEV
  TEEGVRFRSPYDGNETLLSPEKSVQIQNALGSDIIMQLDDVVSSTVTGPRVEEAMYRSIR
  WLDRCIAAHQRPDKQNLFAIIQGGLDADLRATCLEEMTKRDVPGFAIGGLSGGESKSQFW
  RMVALSTSRLPKDKPRYLMGVGYATDLVVCVALGCDMFDCVFPTRTARFGSALVPTGNLQ
  LRKKVFEKDFGPIDPECTCPTCQKHSRAFLHALLHSDNTAALHHLTVHNIAYQLQLMSAV
  RTSIVEKRFPDFVRDFMGAMYGDPTLCPTWATDALASVGITLG
• Function: Catalytic subunit of the queuine tRNA-ribosyltransferase (TGT) that catalyzes the base-exchange of a guanine (G) residue with queuine (Q) at position 34 (anticodon wobble position) in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr), resulting in the hypermodified nucleoside queuosine (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine). Catalysis occurs through a double-displacement mechanism. The nucleophile active site attacks the C1' of nucleotide 34 to detach the guanine base from the RNA, forming a covalent enzyme-RNA intermediate. The proton acceptor active site deprotonates the incoming queuine, allowing a nucleophilic attack on the C1' of the ribose to form the product. Modification of cytoplasmic tRNAs with queuosine controls the elongation speed of cognate codons, thereby ensuring the correct folding of nascent proteins to maintain proteome integrity.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)
• BioCyc Pathway: MetaCyc:HS05270-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Essential thrombocythemia	DISWWK11	Strong	Genetic Variation	[5]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Biomarker	[10]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[11]
Mycosis fungoides	DIS62RB8	Strong	Biomarker	[12]
Myotonia fluctuans	DISGCBNH	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[13]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[14]
Split hand-foot malformation	DIS8PKGD	Strong	Genetic Variation	[15]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[16]

3 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 Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[26]
Selenium	DM25CGV	Approved	Selenium increases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1).	[30]

References

• [1] What Glues a Homodimer Together: Systematic Analysis of the Stabilizing Effect of an Aromatic Hot Spot in the Protein-Protein Interface of the tRNA-Modifying Enzyme Tgt.ACS Chem Biol. 2015 Aug 21;10(8):1897-907. doi: 10.1021/acschembio.5b00028. Epub 2015 May 26.
• [2] Association of Single-Nucleotide Polymorphisms of CD44 Gene with Susceptibility to Breast Cancer in Chinese Women.Med Sci Monit. 2018 May 11;24:3077-3083. doi: 10.12659/MSM.907422.
• [3] Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1.Clin Endocrinol (Oxf). 2002 Mar;56(3):341-50. doi: 10.1046/j.1365-2265.2002.01475.x.
• [4] KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies.Lung Cancer. 2014 Feb;83(2):163-7. doi: 10.1016/j.lungcan.2013.11.010. Epub 2013 Nov 21.
• [5] Investigation of T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) polymorphisms in essential thrombocythaemia (ET).Hematology. 2017 Jul;22(6):361-367. doi: 10.1080/10245332.2016.1266434. Epub 2016 Dec 17.
• [6] K-ras point mutation occurs in the early stage of carcinogenesis in lung cancer.Br J Cancer. 1998 Mar;77(5):720-3. doi: 10.1038/bjc.1998.118.
• [7] Association of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) polymorphisms with susceptibility and disease progression of HBV infection.PLoS One. 2014 May 27;9(5):e98280. doi: 10.1371/journal.pone.0098280. eCollection 2014.
• [8] Association between single-nucleotide polymorphisms in selectin genes and immunoglobulin A nephropathy.Am J Hum Genet. 2002 Mar;70(3):781-6. doi: 10.1086/339077. Epub 2002 Feb 1.
• [9] Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer.Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):571-5. doi: 10.1158/1055-9965.EPI-04-0472.
• [10] Detection of codon 12 K-ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas.Br J Cancer. 2000 Jan;82(2):412-7. doi: 10.1054/bjoc.1999.0935.
• [11] Homodimer Architecture of QTRT2, the Noncatalytic Subunit of the Eukaryotic tRNA-Guanine Transglycosylase.Biochemistry. 2018 Jul 3;57(26):3953-3965. doi: 10.1021/acs.biochem.8b00294. Epub 2018 Jun 14.
• [12] K-Ras mutant fraction in A/J mouse lung increases as a function of benzo[a]pyrene dose.Environ Mol Mutagen. 2010 Mar;51(2):146-55. doi: 10.1002/em.20513.
• [13] Oncomutations as biomarkers of cancer risk.Environ Mol Mutagen. 2010 Oct-Dec;51(8-9):836-50. doi: 10.1002/em.20600.
• [14] Identification of a novel pancreatitis-associated missense mutation, R116C, in the human cationic trypsinogen gene (PRSS1).Mol Genet Metab. 2001 Nov;74(3):342-4. doi: 10.1006/mgme.2001.3246.
• [15] TP63 mutation and clefting modifier genes in an EEC syndrome family.Clin Genet. 2004 Sep;66(3):217-22. doi: 10.1111/j.1399-0004.2004.00287.x.
• [16] Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] 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.
• [20] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] 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.
• [25] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [26] 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.
• [27] 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.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.