Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOMKF5)

• DOT Name: E3 ubiquitin-protein ligase Itchy homolog (ITCH)
• Synonyms: Itch; EC 2.3.2.26; Atrophin-1-interacting protein 4; AIP4; HECT-type E3 ubiquitin transferase Itchy homolog; NFE2-associated polypeptide 1; NAPP1
• Gene Name: ITCH
• Related Disease: Syndromic multisystem autoimmune disease due to ITCH deficiency
• UniProt ID: ITCH_HUMAN
• PDB ID: 2DMV; 2KYK; 2NQ3; 2P4R; 2YSF; 3TUG; 4ROF; 5C7M; 5CQ2; 5DWS; 5DZD; 5SXP
• EC Number: 2.3.2.26
• Pfam ID: PF00168 ; PF00632 ; PF00397
• Sequence:
  MSDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNT
  NSPKWKQPLTVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEEVVVTL
  QLGGDKEPTETIGDLSICLDGLQLESEVVTNGETTCSENGVSLCLPRLECNSAISAHCNL
  CLPGLSDSPISASRVAGFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNS
  PSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSATSESDGSSTGSLPPTNTNTNTSEG
  ATSGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPL
  PPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIY
  GNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPL
  PEGWEMRFTVDGIPYFVDHNRRTTTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQ
  QLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLL
  SHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFS
  LPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECDLEMYFSVDKEILGEIKSHDL
  KPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEV
  LLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVG
  GFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGF
  GQE
• Function: Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. Involved in the control of inflammatory signaling pathways. Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Mediates JUN ubiquitination and degradation. Mediates JUNB ubiquitination and degradation. Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation. Involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity. Ubiquitinates PI4K2A and negatively regulates its catalytic activity. Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. Ubiquitinates SNX9. Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 proteasomal degradation. Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  Notch sig.ling pathway (hsa04330)
  TNF sig.ling pathway (hsa04668)
  Non-alcoholic fatty liver disease (hsa04932)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of necroptotic cell death (R-HSA-5675482)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  Antigen processing (R-HSA-983168)
  Downregulation of ERBB4 signaling (R-HSA-1253288)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic multisystem autoimmune disease due to ITCH deficiency	DIS3B49Y	Strong	Autosomal recessive	[1]

9 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 E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[7]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[12]

2 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 decreases the methylation of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of E3 ubiquitin-protein ligase Itchy homolog (ITCH).	[11]

References

• [1] Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet. 2010 Mar 12;86(3):447-53. doi: 10.1016/j.ajhg.2010.01.028. Epub 2010 Feb 18.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] 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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [9] 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.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.