Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMCR6JM)

• DOT Name: OTU domain-containing protein 5 (OTUD5)
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme A; DUBA
• Gene Name: OTUD5
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Multiple congenital anomalies-neurodevelopmental syndrome, X-linked
  Multiple congenital anomalies/dysmorphic syndrome
  Neoplasm
  Small-cell lung cancer
• UniProt ID: OTUD5_HUMAN
• PDB ID: 3PFY; 3TMO; 3TMP
• EC Number: 3.4.19.12
• Pfam ID: PF02338
• Sequence:
  MTILPKKKPPPPDADPANEPPPPGPMPPAPRRGGGVGVGGGGTGVGGGDRDRDSGVVGAR
  PRASPPPQGPLPGPPGALHRWALAVPPGAVAGPRPQQASPPPCGGPGGPGGGPGDALGAA
  AAGVGAAGVVVGVGGAVGVGGCCSGPGHSKRRRQAPGVGAVGGGSPEREEVGAGYNSEDE
  YEAAAARIEAMDPATVEQQEHWFEKALRDKKGFIIKQMKEDGACLFRAVADQVYGDQDMH
  EVVRKHCMDYLMKNADYFSNYVTEDFTTYINRKRKNNCHGNHIEMQAMAEMYNRPVEVYQ
  YSTGTSAVEPINTFHGIHQNEDEPIRVSYHRNIHYNSVVNPNKATIGVGLGLPSFKPGFA
  EQSLMKNAIKTSEESWIEQQMLEDKKRATDWEATNEAIEEQVARESYLQWLRDQEKQARQ
  VRGPSQPRKASATCSSATAAASSGLEEWTSRSPRQRSSASSPEHPELHAELGMKPPSPGT
  VLALAKPPSPCAPGTSSQFSAGADRATSPLVSLYPALECRALIQQMSPSAFGLNDWDDDE
  ILASVLAVSQQEYLDSMKKNKVHRDPPPDKS
• Function: Deubiquitinating enzyme that functions as a negative regulator of the innate immune system. Has peptidase activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. Can also cleave 'Lys-11'-linked ubiquitin chains (in vitro). Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production. Controls neuroectodermal differentiation through cleaving 'Lys-48'-linked ubiquitin chains to counteract degradation of select chromatin regulators such as ARID1A, HDAC2 and HCF1. Acts as a positive regulator of mTORC1 and mTORC2 signaling following phosphorylation by MTOR: acts by mediating deubiquitination of BTRC, leading to its stability.
• Tissue Specificity: Expressed in various tissues, including the liver and placenta, as well as in peripheral blood leukocytes.
• KEGG Pathway: RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway:
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Ovarian tumor domain proteases (R-HSA-5689896)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Biomarker	[1]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[1]
Multiple congenital anomalies-neurodevelopmental syndrome, X-linked	DISO5NMO	Strong	X-linked	[2]
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Moderate	X-linked	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[4]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of OTU domain-containing protein 5 (OTUD5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of OTU domain-containing protein 5 (OTUD5).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of OTU domain-containing protein 5 (OTUD5).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of OTU domain-containing protein 5 (OTUD5).	[9]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of OTU domain-containing protein 5 (OTUD5).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of OTU domain-containing protein 5 (OTUD5).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of OTU domain-containing protein 5 (OTUD5).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of OTU domain-containing protein 5 (OTUD5).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of OTU domain-containing protein 5 (OTUD5).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of OTU domain-containing protein 5 (OTUD5).	[7]

References

• [1] Effect of Deubiquitinase Ovarian Tumor Domain-Containing Protein 5 (OTUD5) on Radiosensitivity of Cervical Cancer by Regulating the Ubiquitination of Akt and its Mechanism.Med Sci Monit. 2019 May 10;25:3469-3475. doi: 10.12659/MSM.912904.
• [2] Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019 Jul;24(7):1027-1039. doi: 10.1038/s41380-017-0012-2. Epub 2018 Jan 4.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Promiximab-duocarmycin, a new CD56 antibody-drug conjugates, is highly efficacious in small cell lung cancer xenograft models.Oncotarget. 2017 Dec 26;9(4):5197-5207. doi: 10.18632/oncotarget.23708. eCollection 2018 Jan 12.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.