Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV21BN1)

• DOT Name: Tudor and KH domain-containing protein (TDRKH)
• Synonyms: Tudor domain-containing protein 2
• Gene Name: TDRKH
• Related Disease:
  Coronary heart disease
  Asthma
• UniProt ID: TDRKH_HUMAN
• PDB ID: 2DIQ; 3FDR; 5J39; 6B57; 6PI7
• Pfam ID: PF00013 ; PF00567
• Sequence:
  MSTERTSWTSLSTIQKIALGLGIPASATVAYILYRRYRESREERLTFVGEDDIEIEMRVP
  QEAVKLIIGRQGANIKQLRKQTGARIDVDTEDVGDERVLLISGFPVQVCKAKAAIHQILT
  ENTPVSEQLSVPQRSVGRIIGRGGETIRSICKASGAKITCDKESEGTLLLSRLIKISGTQ
  KEVAAAKHLILEKVSEDEELRKRIAHSAETRVPRKQPISVRREDMTEPGGAGEPALWKNT
  SSSMEPTAPLVTPPPKGGGDMAVVVSKEGSWEKPSDDSFQKSEAQAIPEMPMFEIPSPDF
  SFHADEYLEVYVSASEHPNHFWIQIVGSRSLQLDKLVNEMTQHYENSVPEDLTVHVGDIV
  AAPLPTNGSWYRARVLGTLENGNLDLYFVDFGDNGDCPLKDLRALRSDFLSLPFQAIECS
  LARIAPSGDQWEEEALDEFDRLTHCADWKPLVAKISSYVQTGISTWPKIYLYDTSNGKKL
  DIGLELVHKGYAIELPEDIEENRAVPDMLKDMATETDASLSTLLTETKKSSGEITHTLSC
  LSLSEAASMSGDDNLEDDYLL
• Function: Participates in the primary piRNA biogenesis pathway and is required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for the germline integrity. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Required for the final steps of primary piRNA biogenesis by participating in the processing of 31-37 nt intermediates into mature piRNAs. May act in pi-bodies and piP-bodies by transferring piRNA precursors or intermediates to or between these granules.
• Reactome Pathway: PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[1]
Asthma	DISW9QNS	Limited	Genetic Variation	[2]

10 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 Tudor and KH domain-containing protein (TDRKH).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tudor and KH domain-containing protein (TDRKH).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tudor and KH domain-containing protein (TDRKH).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tudor and KH domain-containing protein (TDRKH).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Tudor and KH domain-containing protein (TDRKH).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tudor and KH domain-containing protein (TDRKH).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Tudor and KH domain-containing protein (TDRKH).	[9]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Tudor and KH domain-containing protein (TDRKH).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tudor and KH domain-containing protein (TDRKH).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tudor and KH domain-containing protein (TDRKH).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tudor and KH domain-containing protein (TDRKH).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tudor and KH domain-containing protein (TDRKH).	[13]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Tudor and KH domain-containing protein (TDRKH).	[15]

References

• [1] 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.
• [2] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [10] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [11] 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.
• [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] 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.
• [15] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.