Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZOQ2ZM)

• DOT Name: Vesicle-associated membrane protein 2
• Synonyms: VAMP-2; Synaptobrevin-2
• Gene Name: VAMP2
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements
• UniProt ID: VAMP2_HUMAN
• PDB ID: 3FIE; 3FII; 3RK2; 3RK3; 3RL0; 7UDC
• Pfam ID: PF00957
• Sequence:
  MSATAATAPPAAPAGEGGPPAPPPNLTSNRRLQQTQAQVDEVVDIMRVNVDKVLERDQKL
  SELDDRADALQAGASQFETSAAKLKRKYWWKNLKMMIILGVICAIILIIIIVYFST
• Function: Involved in the targeting and/or fusion of transport vesicles to their target membrane. Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.
• Tissue Specificity: Nervous system and skeletal muscle.
• KEGG Pathway:
  S.RE interactions in vesicular transport (hsa04130)
  Sy.ptic vesicle cycle (hsa04721)
  Insulin secretion (hsa04911)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  trans-Golgi Network Vesicle Budding (R-HSA-199992)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  Insulin processing (R-HSA-264876)
  Regulation of insulin secretion (R-HSA-422356)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Other interleukin signaling (R-HSA-449836)
  Toxicity of botulinum toxin type D (botD) (R-HSA-5250955)
  Toxicity of botulinum toxin type B (botB) (R-HSA-5250958)
  Toxicity of botulinum toxin type F (botF) (R-HSA-5250981)
  Toxicity of tetanus toxin (tetX) (R-HSA-5250982)
  Toxicity of botulinum toxin type G (botG) (R-HSA-5250989)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[1]
Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements	DISOKUGK	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vesicle-associated membrane protein 2.	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Vesicle-associated membrane protein 2.	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vesicle-associated membrane protein 2.	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Vesicle-associated membrane protein 2.	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Vesicle-associated membrane protein 2.	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Vesicle-associated membrane protein 2.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Vesicle-associated membrane protein 2.	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Vesicle-associated membrane protein 2.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Vesicle-associated membrane protein 2.	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Vesicle-associated membrane protein 2.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Vesicle-associated membrane protein 2.	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Vesicle-associated membrane protein 2.	[9]

References

• [1] Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment. Am J Hum Genet. 2019 Apr 4;104(4):721-730. doi: 10.1016/j.ajhg.2019.02.016. Epub 2019 Mar 28.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
• [6] 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.
• [7] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.