Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHGS2VA)

• DOT Name: (E3-independent) E2 ubiquitin-conjugating enzyme
• Synonyms: EC 2.3.2.24; E2/E3 hybrid ubiquitin-protein ligase UBE2O; Ubiquitin carrier protein O; Ubiquitin-conjugating enzyme E2 O; Ubiquitin-conjugating enzyme E2 of 230 kDa; Ubiquitin-conjugating enzyme E2-230K; Ubiquitin-protein ligase O
• Gene Name: UBE2O
• UniProt ID: UBE2O_HUMAN
• PDB ID: 7UN3; 7UN6
• EC Number: 2.3.2.24
• Pfam ID: PF00179
• Sequence:
  MADPAAPTPAAPAPAQAPAPAPEAVPAPAAAPVPAPAPASDSASGPSSDSGPEAGSQRLL
  FSHDLVSGRYRGSVHFGLVRLIHGEDSDSEGEEEGRGSSGCSEAGGAGHEEGRASPLRRG
  YVRVQWYPEGVKQHVKETKLKLEDRSVVPRDVVRHMRSTDSQCGTVIDVNIDCAVKLIGT
  NCIIYPVNSKDLQHIWPFMYGDYIAYDCWLGKVYDLKNQIILKLSNGARCSMNTEDGAKL
  YDVCPHVSDSGLFFDDSYGFYPGQVLIGPAKIFSSVQWLSGVKPVLSTKSKFRVVVEEVQ
  VVELKVTWITKSFCPGGTDSVSPPPSVITQENLGRVKRLGCFDHAQRQLGERCLYVFPAK
  VEPAKIAWECPEKNCAQGEGSMAKKVKRLLKKQVVRIMSCSPDTQCSRDHSMEDPDKKGE
  SKTKSEAESASPEETPDGSASPVEMQDEGAEEPHEAGEQLPPFLLKEGRDDRLHSAEQDA
  DDEAADDTDDTSSVTSSASSTTSSQSGSGTSRKKSIPLSIKNLKRKHKRKKNKITRDFKP
  GDRVAVEVVTTMTSADVMWQDGSVECNIRSNDLFPVHHLDNNEFCPGDFVVDKRVQSCPD
  PAVYGVVQSGDHIGRTCMVKWFKLRPSGDDVELIGEEEDVSVYDIADHPDFRFRTTDIVI
  RIGNTEDGAPHKEDEPSVGQVARVDVSSKVEVVWADNSKTIILPQHLYNIESEIEESDYD
  SVEGSTSGASSDEWEDDSDSWETDNGLVEDEHPKIEEPPIPPLEQPVAPEDKGVVISEEA
  ATAAVQGAVAMAAPMAGLMEKAGKDGPPKSFRELKEAIKILESLKNMTVEQLLTGSPTSP
  TVEPEKPTREKKFLDDIKKLQENLKKTLDNVAIVEEEKMEAVPDVERKEDKPEGQSPVKA
  EWPSETPVLCQQCGGKPGVTFTSAKGEVFSVLEFAPSNHSFKKIEFQPPEAKKFFSTVRK
  EMALLATSLPEGIMVKTFEDRMDLFSALIKGPTRTPYEDGLYLFDIQLPNIYPAVPPHFC
  YLSQCSGRLNPNLYDNGKVCVSLLGTWIGKGTERWTSKSSLLQVLISIQGLILVNEPYYN
  EAGFDSDRGLQEGYENSRCYNEMALIRVVQSMTQLVRRPPEVFEQEIRQHFSTGGWRLVN
  RIESWLETHALLEKAQALPNGVPKASSSPEPPAVAELSDSGQQEPEDGGPAPGEASQGSD
  SEGGAQGLASASRDHTDQTSETAPDASVPPSVKPKKRRKSYRSFLPEKSGYPDIGFPLFP
  LSKGFIKSIRGVLTQFRAALLEAGMPECTEDK
• Function: E2/E3 hybrid ubiquitin-protein ligase that displays both E2 and E3 ligase activities and mediates monoubiquitination of target proteins. Negatively regulates TRAF6-mediated NF-kappa-B activation independently of its E2 activity. Acts as a positive regulator of BMP7 signaling by mediating monoubiquitination of SMAD6, thereby regulating adipogenesis. Mediates monoubiquitination at different sites of the nuclear localization signal (NLS) of BAP1, leading to cytoplasmic retention of BAP1. Also able to monoubiquitinate the NLS of other chromatin-associated proteins, such as INO80 and CXXC1, affecting their subcellular location. Acts as a regulator of retrograde transport by assisting the TRIM27:MAGEL2 E3 ubiquitin ligase complex to mediate 'Lys-63'-linked ubiquitination of WASHC1, leading to promote endosomal F-actin assembly.
• Tissue Specificity: Predominantly expressed in skeletal muscle and heart.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway: Antigen processing (R-HSA-983168)
• BioCyc Pathway: MetaCyc:HS10987-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[5]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[6]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[6]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of (E3-independent) E2 ubiquitin-conjugating enzyme.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of (E3-independent) E2 ubiquitin-conjugating enzyme.	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of (E3-independent) E2 ubiquitin-conjugating enzyme.	[8]

References

• [1] 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.
• [2] 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.
• [3] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [4] 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.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.