Details of Drug Off-Target (DOT)

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

• DOT Name: Ubiquitin-conjugating enzyme E2 T
• Synonyms: EC 2.3.2.23; Cell proliferation-inducing gene 50 protein; E2 ubiquitin-conjugating enzyme T; Ubiquitin carrier protein T; Ubiquitin-protein ligase T
• Gene Name: UBE2T
• Related Disease:
  Fanconi anemia complementation group T
  Fanconi's anemia
• UniProt ID: UBE2T_HUMAN
• PDB ID: 1YH2; 4CCG; 5NGZ; 5OJJ; 6R75; 7KZR; 7KZS; 7KZT; 7KZV; 8JVE; 8JVL
• EC Number: 2.3.2.23
• Pfam ID: PF00179
• Sequence:
  MQRASRLKRELHMLATEPPPGITCWQDKDQMDDLRAQILGGANTPYEKGVFKLEVIIPER
  YPFEPPQIRFLTPIYHPNIDSAGRICLDVLKLPPKGAWRPSLNIATVLTSIQLLMSEPNP
  DDPLMADISSEFKYNKPAFLKNARQWTEKHARQKQKADEEEMLDNLPEAGDSRVHNSTQK
  RKASQLVGIEKKFHPDV
• Function: Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes monoubiquitination. Involved in mitomycin-C (MMC)-induced DNA repair. Acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway. Also mediates monoubiquitination of FANCL and FANCI. May contribute to ubiquitination and degradation of BRCA1. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11'-, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Synthesis of active ubiquitin (R-HSA-8866652)
  Fanconi Anemia Pathway (R-HSA-6783310)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group T	DIS1D86R	Strong	Autosomal recessive	[1]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ubiquitin-conjugating enzyme E2 T.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ubiquitin-conjugating enzyme E2 T.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ubiquitin-conjugating enzyme E2 T.	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ubiquitin-conjugating enzyme E2 T.	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Ubiquitin-conjugating enzyme E2 T.	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[15]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[16]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[18]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ubiquitin-conjugating enzyme E2 T.	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin-conjugating enzyme E2 T.	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ubiquitin-conjugating enzyme E2 T.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ubiquitin-conjugating enzyme E2 T.	[21]

References

• [1] Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am J Hum Genet. 2015 Jun 4;96(6):1001-7. doi: 10.1016/j.ajhg.2015.04.022.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [17] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.