Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMC6F3Y)

• DOT Name: NEDD8-activating enzyme E1 regulatory subunit (NAE1)
• Synonyms: Amyloid beta precursor protein-binding protein 1, 59 kDa; APP-BP1; Amyloid protein-binding protein 1; Proto-oncogene protein 1
• Gene Name: NAE1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Cardiac failure
  Congestive heart failure
  Exanthem
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Pancreatic cancer
  Promyelocytic leukaemia
  Uveal Melanoma
  Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
  Non-small-cell lung cancer
• UniProt ID: ULA1_HUMAN
• PDB ID: 1R4M; 1R4N; 1TT5; 1YOV; 2NVU; 3DBH; 3DBL; 3DBR; 3GZN
• Pfam ID: PF00899
• Sequence:
  MAQLGKLLKEQKYDRQLRLWGDHGQEALESAHVCLINATATGTEILKNLVLPGIGSFTII
  DGNQVSGEDAGNNFFLQRSSIGKNRAEAAMEFLQELNSDVSGSFVEESPENLLDNDPSFF
  CRFTVVVATQLPESTSLRLADVLWNSQIPLLICRTYGLVGYMRIIIKEHPVIESHPDNAL
  EDLRLDKPFPELREHFQSYDLDHMEKKDHSHTPWIVIIAKYLAQWYSETNGRIPKTYKEK
  EDFRDLIRQGILKNENGAPEDEENFEEAIKNVNTALNTTQIPSSIEDIFNDDRCINITKQ
  TPSFWILARALKEFVAKEGQGNLPVRGTIPDMIADSGKYIKLQNVYREKAKKDAAAVGNH
  VAKLLQSIGQAPESISEKELKLLCSNSAFLRVVRCRSLAEEYGLDTINKDEIISSMDNPD
  NEIVLYLMLRAVDRFHKQQGRYPGVSNYQVEEDIGKLKSCLTGFLQEYGLSVMVKDDYVH
  EFCRYGAAEPHTIAAFLGGAAAQEVIKIITKQFVIFNNTYIYSGMSQTSATFQL
• Function: Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. The covalent attachment of NEDD8 to target proteins is known as 'neddylation' and the process is involved in the regulation of cell growth, viability and development.
• Tissue Specificity: Ubiquitous in fetal tissues. Expressed throughout the adult brain.
• KEGG Pathway: Alzheimer disease (hsa05010)
• Reactome Pathway: Neddylation (R-HSA-8951664)
• BioCyc Pathway: MetaCyc:ENSG00000159593-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Exanthem	DISAFOQN	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[6]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[1]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[7]
Uveal Melanoma	DISA7ZGL	Strong	Altered Expression	[8]
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia	DIS91NG6	Limited	Autosomal recessive	[9]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	NEDD8-activating enzyme E1 regulatory subunit (NAE1) affects the response to substance of Afimoxifene.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of NEDD8-activating enzyme E1 regulatory subunit (NAE1).	[16]

References

• [1] An overactive neddylation pathway serves as a therapeutic target and MLN4924 enhances the anticancer activity of cisplatin in pancreatic cancer.Oncol Lett. 2019 Sep;18(3):2724-2732. doi: 10.3892/ol.2019.10596. Epub 2019 Jul 9.
• [2] Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis.J Neurosci. 2007 Jul 4;27(27):7141-53. doi: 10.1523/JNEUROSCI.4599-06.2007.
• [3] Neddylation mediates ventricular chamber maturation through repression of Hippo signaling.Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4101-E4110. doi: 10.1073/pnas.1719309115. Epub 2018 Apr 9.
• [4] An evaluation of single nucleotide polymorphisms used to differentiate vaccine and wild type strains of varicella-zoster virus.J Med Virol. 2005 Jan;75(1):174-80. doi: 10.1002/jmv.20253.
• [5] Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib.Oncol Rep. 2019 Jun;41(6):3257-3269. doi: 10.3892/or.2019.7098. Epub 2019 Apr 4.
• [6] Inhibition of Neddylation Modification Sensitizes Pancreatic Cancer Cells to Gemcitabine.Neoplasia. 2017 Jun;19(6):509-518. doi: 10.1016/j.neo.2017.04.003. Epub 2017 May 20.
• [7] Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells.Int J Med Sci. 2018 Apr 3;15(7):674-681. doi: 10.7150/ijms.23782. eCollection 2018.
• [8] Neddylation Blockade Diminishes Hepatic Metastasis by Dampening Cancer Stem-Like Cells and Angiogenesis in Uveal Melanoma.Clin Cancer Res. 2018 Aug 1;24(15):3741-3754. doi: 10.1158/1078-0432.CCR-17-1703. Epub 2017 Dec 12.
• [9] 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.
• [10] DNA methylation of multiple genes and clinicopathological relationship of non-small cell lung cancers.Oncol Rep. 2004 Jul;12(1):177-80.
• [11] 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.
• [12] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.