Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8C37XH)

• DOT Name: NEDD8 (NEDD8)
• Synonyms: Neddylin; Neural precursor cell expressed developmentally down-regulated protein 8; NEDD-8; Ubiquitin-like protein Nedd8
• Gene Name: NEDD8
• UniProt ID: NEDD8_HUMAN
• PDB ID: 1NDD; 1R4M; 1R4N; 1XT9; 2BKR; 2KO3; 2N7K; 2NVU; 3DBH; 3DBL; 3DBR; 3DQV; 3GZN; 4F8C; 4FBJ; 4HCP; 4P5O; 6R7F; 6R7I; 6TTU; 7B5L; 7B5N; 7ONI; 8B3I; 8CAF; 8H38
• Pfam ID: PF00240
• Sequence:
  MLIKVKTLTGKEIEIDIEPTDKVERIKERVEEKEGIPPQQQRLIYSGKQMNDEKTAADYK
  ILGGSVLHLVLALRGGGGLRQ
• Function: Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis via its conjugation to a limited number of cellular proteins, such as cullins or p53/TP53. Attachment of NEDD8 to cullins is critical for the recruitment of E2 to the cullin-RING-based E3 ubiquitin-protein ligase complex, thus facilitating polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins. Attachment of NEDD8 to p53/TP53 inhibits p53/TP53 transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M.
• Tissue Specificity: Highly expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, ovary, colon and leukocytes.
• Reactome Pathway:
  UCH proteinases (R-HSA-5689603)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Neddylation (R-HSA-8951664)
  Iron uptake and transport (R-HSA-917937)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)

Molecular Interaction Atlas (MIA) of This DOT

9 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 NEDD8 (NEDD8).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NEDD8 (NEDD8).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NEDD8 (NEDD8).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NEDD8 (NEDD8).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of NEDD8 (NEDD8).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of NEDD8 (NEDD8).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of NEDD8 (NEDD8).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of NEDD8 (NEDD8).	[8]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NEDD8 (NEDD8).	[9]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):197-210. doi: 10.1016/j.taap.2006.12.030. Epub 2007 Jan 9.
• [6] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [9] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.