Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKRJ2ZT)

• DOT Name: Vesicle-fusing ATPase (NSF)
• Synonyms: EC 3.6.4.6; N-ethylmaleimide-sensitive fusion protein; NEM-sensitive fusion protein; Vesicular-fusion protein NSF
• Gene Name: NSF
• Related Disease:
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Anxiety
  Crohn disease
  Cytomegalovirus infection
  Epilepsy
  Infantile epileptic-dyskinetic encephalopathy
  Ovarian neoplasm
  Primary biliary cholangitis
  Temporal lobe epilepsy
  Frontotemporal dementia
  Progressive supranuclear palsy
  Alopecia
  Cocaine addiction
  Developmental and epileptic encephalopathy 96
  Intellectual disability
  Malignant rhabdoid tumour
  Neuroblastoma
• UniProt ID: NSF_HUMAN
• PDB ID: 6KZQ
• EC Number: 3.6.4.6
• Pfam ID: PF00004 ; PF17862 ; PF02933 ; PF02359
• Sequence:
  MAGRSMQAARCPTDELSLTNCAVVNEKDFQSGQHVIVRTSPNHRYTFTLKTHPSVVPGSI
  AFSLPQRKWAGLSIGQEIEVSLYTFDKAKQCIGTMTIEIDFLQKKSIDSNPYDTDKMAAE
  FIQQFNNQAFSVGQQLVFSFNEKLFGLLVKDIEAMDPSILKGEPATGKRQKIEVGLVVGN
  SQVAFEKAENSSLNLIGKAKTKENRQSIINPDWNFEKMGIGGLDKEFSDIFRRAFASRVF
  PPEIVEQMGCKHVKGILLYGPPGCGKTLLARQIGKMLNAREPKVVNGPEILNKYVGESEA
  NIRKLFADAEEEQRRLGANSGLHIIIFDEIDAICKQRGSMAGSTGVHDTVVNQLLSKIDG
  VEQLNNILVIGMTNRPDLIDEALLRPGRLEVKMEIGLPDEKGRLQILHIHTARMRGHQLL
  SADVDIKELAVETKNFSGAELEGLVRAAQSTAMNRHIKASTKVEVDMEKAESLQVTRGDF
  LASLENDIKPAFGTNQEDYASYIMNGIIKWGDPVTRVLDDGELLVQQTKNSDRTPLVSVL
  LEGPPHSGKTALAAKIAEESNFPFIKICSPDKMIGFSETAKCQAMKKIFDDAYKSQLSCV
  VVDDIERLLDYVPIGPRFSNLVLQALLVLLKKAPPQGRKLLIIGTTSRKDVLQEMEMLNA
  FSTTIHVPNIATGEQLLEALELLGNFKDKERTTIAQQVKGKKVWIGIKKLLMLIEMSLQM
  DPEYRVRKFLALLREEGASPLDFD
• Function: Required for vesicle-mediated transport. Catalyzes the fusion of transport vesicles within the Golgi cisternae. Is also required for transport from the endoplasmic reticulum to the Golgi stack. Seems to function as a fusion protein required for the delivery of cargo proteins to all compartments of the Golgi stack independent of vesicle origin. Interaction with AMPAR subunit GRIA2 leads to influence GRIA2 membrane cycling.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  GABAergic sy.pse (hsa04727)
  Vasopressin-regulated water reabsorption (hsa04962)
• Reactome Pathway:
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  Intra-Golgi traffic (R-HSA-6811438)
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Biomarker	[1]
Lymphoma	DISN6V4S	Definitive	Biomarker	[1]
Pediatric lymphoma	DIS51BK2	Definitive	Biomarker	[1]
Anxiety	DISIJDBA	Strong	Genetic Variation	[2]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Altered Expression	[5]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[6]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[7]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[8]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[5]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[9]
Progressive supranuclear palsy	DISO5KRQ	moderate	Genetic Variation	[9]
Alopecia	DIS37HU4	Limited	Genetic Variation	[10]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[11]
Developmental and epileptic encephalopathy 96	DISSUX1E	Limited	Autosomal dominant	[12]
Intellectual disability	DISMBNXP	Limited	Biomarker	[6]
Malignant rhabdoid tumour	DIS46HZU	Limited	Altered Expression	[13]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Vesicle-fusing ATPase (NSF).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Vesicle-fusing ATPase (NSF).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Vesicle-fusing ATPase (NSF).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Vesicle-fusing ATPase (NSF).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vesicle-fusing ATPase (NSF).	[18]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Vesicle-fusing ATPase (NSF).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Vesicle-fusing ATPase (NSF).	[20]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Vesicle-fusing ATPase (NSF).	[21]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Vesicle-fusing ATPase (NSF).	[22]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Vesicle-fusing ATPase (NSF).	[21]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Vesicle-fusing ATPase (NSF).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Vesicle-fusing ATPase (NSF).	[23]

References

• [1] Anaplastic plasmacytoma of mouse--establishing parallels between subtypes of mouse and human plasma cell neoplasia.J Pathol. 2010 Jul;221(3):242-7. doi: 10.1002/path.2714.
• [2] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [3] Crohn's disease loci are common targets of protozoa-driven selection.Mol Biol Evol. 2013 May;30(5):1077-87. doi: 10.1093/molbev/mst020. Epub 2013 Feb 6.
• [4] NSF, Unc-18-1, dynamin-1 and HSP90 are inclusion body components in neuronal intranuclear inclusion disease identified by anti-SUMO-1-immunocapture.Acta Neuropathol. 2008 Dec;116(6):603-14. doi: 10.1007/s00401-008-0437-4. Epub 2008 Oct 3.
• [5] ATPase N-ethylmaleimide-sensitive Fusion Protein: A Novel Key Player for Causing Spontaneous Network Excitation in Human Temporal Lobe Epilepsy.Neuroscience. 2018 Feb 10;371:371-383. doi: 10.1016/j.neuroscience.2017.12.013. Epub 2017 Dec 17.
• [6] De novo NSF mutations cause early infantile epileptic encephalopathy. Ann Clin Transl Neurol. 2019 Nov;6(11):2334-2339. doi: 10.1002/acn3.50917. Epub 2019 Nov 1.
• [7] Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.PLoS Genet. 2013;9(3):e1003212. doi: 10.1371/journal.pgen.1003212. Epub 2013 Mar 27.
• [8] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [9] Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia.Acta Neuropathol. 2017 May;133(5):825-837. doi: 10.1007/s00401-017-1693-y. Epub 2017 Mar 7.
• [10] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [11] A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence.Sci Rep. 2016 Aug 8;6:31033. doi: 10.1038/srep31033.
• [12] 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.
• [13] Malignant rhabdoid tumor shows incomplete neural characteristics as revealed by expression of SNARE complex.J Neurosci Res. 2002 Sep 1;69(5):642-52. doi: 10.1002/jnr.10330.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [20] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [21] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [22] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.