Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZQX0F)

• DOT Name: tRNA (THADA)
• Synonyms: 32-2'-O)-methyltransferase regulator THADA (Gene inducing thyroid adenomas protein; Thyroid adenoma-associated protein
• Gene Name: THADA
• Related Disease:
  Adenoma
  Cardiovascular disease
  Endometrial carcinoma
  Isolated cleft lip
  Nasopharyngeal carcinoma
  Neoplasm
  Obesity
  Prostate cancer
  Prostate carcinoma
  Coronary heart disease
  Type-1/2 diabetes
  Alopecia
  Androgenetic alopecia
  Ankylosing spondylitis
  Baldness, male pattern
  Crohn disease
  Inflammatory bowel disease
  Non-insulin dependent diabetes
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: THADA_HUMAN
• PDB ID: 5T6Y
• Pfam ID: PF10350
• Sequence:
  MGVKKKKEMQVAALTICHQDLETLKSFADVEGKNLASLLLHCVQLTDGVSQIHYIKQIVP
  LLEKADKNGMCDPTIQSCLDILAGIYLSLSLKNPLKKVLASSLNSLPDFFLPEAMHRFTS
  RLQEELNTTDLYSYRKVTDNISSCMENFNLGRASVNNLLKNVLHFLQKSLIEILEENRKC
  AGNHIIQTQLMNDLLVGIRVSMMLVQKVQDFQGNLWKTSDSPIWQNMCGLLSIFTKVLSD
  DDLLQTVQSTSGLAIILFIKTMFHPSEKIPHLISSVLLRSVDCTSVPEWFMSSCRSLCCG
  DISQSAVLFLCQGTLAMLDWQNGSMGRSGEALLLDTAHVLFTLSSQIKEPTLEMFLSRIL
  ASWTNSAIQVLESSSPSLTDSLNGNSSIVGRLLEYVYTHWEHPLDALRHQTKIMFKNLLQ
  MHRLTVEGADFVPDPFFVELTESLLRLEWHIKGKYTCLGCLVECIGVEHILAIDKTIPSQ
  ILEVMGDQSLVPYASDLLETMFRNHKSHLKSQTAESSWIDQWHETWVSPLLFILCEGNLD
  QKSYVIDYYLPKLLSYSPESLQYMVKILQTSIDAKTGQEQSFPSLGSCNSRGALGALMAC
  LRIARAHGHLQSATDTWENLVSDARIKQGLIHQHCQVRIDTLGLLCESNRSTEIVSMEEM
  QWIQFFITYNLNSQSPGVRQQICSLLKKLFCRIQESSQVLYKLEQSKSKREPENELTKQH
  PSVSLQQYKNFMSSICNSLFEALFPGSSYSTRFSALTILGSIAEVFHVPEGRIYTVYQLS
  HDIDVGRFQTLMECFTSTFEDVKILAFDLLMKLSKTAVHFQDSGKLQGLFQAALELSTST
  KPYDCVTASYLLNFLIWQDALPSSLSAYLTQQVACDNGDRPAAVVERNTLMVIKCLMENL
  EEEVSQAENSLLQAAAAFPMYGRVHCITGALQKLSLNSLQLVSEWRPVVEKLLLMSYRLS
  TVVSPVIQSSSPEGLIPMDTDSESASRLQMILNEIQPRDTNDYFNQAKILKEHDSFDMKD
  LNASVVNIDTSTEIKGKEVKTCDVTAQMVLVCCWRSMKEVALLLGMLCQLLPMQPVPESS
  DGLLTVEQVKEIGDYFKQHLLQSRHRGAFELAYTGFVKLTEVLNRCPNVSLQKLPEQWLW
  SVLEEIKCSDPSSKLCATRRSAGIPFYIQALLASEPKKGRMDLLKITMKELISLAGPTDD
  IQSTVPQVHALNILRALFRDTRLGENIIPYVADGAKAAILGFTSPVWAVRNSSTLLFSAL
  ITRIFGVKRAKDEHSKTNRMTGREFFSRFPELYPFLLKQLETVANTVDSDMGEPNRHPSM
  FLLLLVLERLYASPMDGTSSALSMGPFVPFIMRCGHSPVYHSREMAARALVPFVMIDHIP
  NTIRTLLSTLPSCTDQCFRQNHIHGTLLQVFHLLQAYSDSKHGTNSDFQHELTDITVCTK
  AKLWLAKRQNPCLVTRAVYIDILFLLTCCLNRSAKDNQPVLESLGFWEEVRGIISGSELI
  TGFPWAFKVPGLPQYLQSLTRLAIAAVWAAAAKSGERETNVPISFSQLLESAFPEVRSLT
  LEALLEKFLAAASGLGEKGVPPLLCNMGEKFLLLAMKENHPECFCKILKILHCMDPGEWL
  PQTEHCVHLTPKEFLIWTMDIASNERSEIQSVALRLASKVISHHMQTCVENRELIAAELK
  QWVQLVILSCEDHLPTESRLAVVEVLTSTTPLFLTNPHPILELQDTLALWKCVLTLLQSE
  EQAVRDAATETVTTAMSQENTCQSTEFAFCQVDASIALALALAVLCDLLQQWDQLAPGLP
  ILLGWLLGESDDLVACVESMHQVEEDYLFEKAEVNFWAETLIFVKYLCKHLFCLLSKSGW
  RPPSPEMLCHLQRMVSEQCHLLSQFFRELPPAAEFVKTVEFTRLRIQEERTLACLRLLAF
  LEGKEGEDTLVLSVWDSYAESRQLTLPRTEAAC
• Function: Together with methyltransferase FTSJ1, methylates the 2'-O-ribose of nucleotides at position 32 of the anticodon loop of substrate tRNAs.
• Tissue Specificity: Expressed in pancreas, adrenal medulla, thyroid, adrenal cortex, testis, thymus, small intestine and stomach.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[3]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[8]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[11]
Alopecia	DIS37HU4	Limited	Genetic Variation	[12]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[13]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[14]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[13]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[15]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[15]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[16]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[14]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[14]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of tRNA (THADA).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (THADA).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of tRNA (THADA).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA (THADA).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of tRNA (THADA).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of tRNA (THADA).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of tRNA (THADA).	[23]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of tRNA (THADA).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of tRNA (THADA).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA (THADA).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of tRNA (THADA).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of tRNA (THADA).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA (THADA).	[29]

References

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• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Variants in DENND1A and LHCGR are associated with endometrioid adenocarcinoma.Gynecol Oncol. 2012 Nov;127(2):403-5. doi: 10.1016/j.ygyno.2012.08.007. Epub 2012 Aug 14.
• [4] Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.Nat Genet. 2012 Sep;44(9):968-71. doi: 10.1038/ng.2360. Epub 2012 Aug 5.
• [5] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [6] Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).Virchows Arch. 2019 Mar;474(3):341-351. doi: 10.1007/s00428-018-02512-6. Epub 2019 Jan 15.
• [7] THADA Regulates the Organismal Balance between Energy Storage and Heat Production.Dev Cell. 2017 Apr 10;41(1):72-81.e6. doi: 10.1016/j.devcel.2017.03.016.
• [8] THADA gene polymorphism and prostate cancer risk: a meta-analysis.Oncol Res Treat. 2014;37(3):106-10. doi: 10.1159/000360206. Epub 2014 Feb 21.
• [9] 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population.Nat Commun. 2019 Sep 27;10(1):4422. doi: 10.1038/s41467-019-12267-6.
• [10] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [11] Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study.Diabetologia. 2013 Oct;56(10):2194-202. doi: 10.1007/s00125-013-2988-8. Epub 2013 Jul 14.
• [12] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [13] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [14] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [15] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [16] Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk.Sci Rep. 2019 Feb 6;9(1):1512. doi: 10.1038/s41598-018-37856-1.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [24] 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.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] 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.
• [27] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.