Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15EP5B)

• DOT Name: Pseudouridylate synthase TRUB1 (TRUB1)
• Synonyms: EC 5.4.99.-; TruB pseudouridine synthase homolog 1; tRNA pseudouridine 55 synthase TRUB1; Psi55 synthase TRUB1; EC 5.4.99.25
• Gene Name: TRUB1
• Related Disease:
  Dyskeratosis congenita
  Dyskeratosis congenita, X-linked
• UniProt ID: TRUB1_HUMAN
• EC Number: 5.4.99.-; 5.4.99.25
• Pfam ID: PF01509
• Sequence:
  MAASEAAVVSSPSLKTDTSPVLETAGTVAAMAATPSARAAAAVVAAAARTGSEARVSKAA
  LATKLLSLSGVFAVHKPKGPTSAELLNRLKEKLLAEAGMPSPEWTKRKKQTLKIGHGGTL
  DSAARGVLVVGIGSGTKMLTSMLSGSKRYTAIGELGKATDTLDSTGRVTEEKPYDKITQE
  DIEGILQKFTGNIMQVPPLYSALKKDGQRLSTLMKRGEVVEAKPARPVTVYSISLQKFQP
  PFFTLDVECGGGFYIRSLVSDIGKELSSCANVLELTRTKQGPFTLEEHALPEDKWTIDDI
  AQSLEHCSSLFPAELALKKSKPESNEQVLSCEYITLNEPKREDDVIKTC
• Function: Pseudouridine synthase that catalyzes pseudouridylation of mRNAs and tRNAs. Mediates pseudouridylation of mRNAs with the consensus sequence 5'-GUUCNANNC-3', harboring a stem-loop structure. Constitutes the major pseudouridine synthase acting on mRNAs. Also catalyzes pseudouridylation of some tRNAs, including synthesis of pseudouridine(55) from uracil-55, in the psi GC loop of a subset of tRNAs. Promotes the processing of pri-let-7 microRNAs (pri-miRNAs) independently of its RNA pseudouridylate synthase activity. Acts by binding to the stem-loop structure on pri-let-7, preventing LIN28-binding (LIN28A and/or LIN28B), thereby enhancing the interaction between pri-let-7 and the microprocessor DGCR8, which mediates miRNA maturation.
• Tissue Specificity: Highly expressed in heart, skeletal muscle and liver. Expressed at lower levels in lung, small intestine, kidney and spleen.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita	DISSXV0K	Strong	Biomarker	[1]
Dyskeratosis congenita, X-linked	DISJ3Y69	Strong	Genetic Variation	[1]

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 Pseudouridylate synthase TRUB1 (TRUB1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pseudouridylate synthase TRUB1 (TRUB1).	[16]

4 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 Pseudouridylate synthase TRUB1 (TRUB1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pseudouridylate synthase TRUB1 (TRUB1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pseudouridylate synthase TRUB1 (TRUB1).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pseudouridylate synthase TRUB1 (TRUB1).	[12]

References

• [1] The human TruB family of pseudouridine synthase genes, including the Dyskeratosis Congenita 1 gene and the novel member TRUB1.Int J Mol Med. 2003 Jun;11(6):697-704.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] 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.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [13] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.