Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIH108W)

• DOT Name: Synaptic vesicle glycoprotein 2C (SV2C)
• Gene Name: SV2C
• Related Disease:
  Neoplasm
  Parkinson disease
  Alzheimer disease
  Breast carcinoma
  Epilepsy
  Huntington disease
  High blood pressure
  Nervous system disease
  Psychotic disorder
  Venous thromboembolism
• UniProt ID: SV2C_HUMAN
• PDB ID: 4JRA; 5JLV; 5MOY; 6ES1; 7UIA; 7UIB
• Pfam ID: PF07690 ; PF13599 ; PF00083
• Sequence:
  MEDSYKDRTSLMKGAKDIAREVKKQTVKKVNQAVDRAQDEYTQRSYSRFQDEEDDDDYYP
  AGETYNGEANDDEGSSEATEGHDEDDEIYEGEYQGIPSMNQAKDSIVSVGQPKGDEYKDR
  RELESERRADEEELAQQYELIIQECGHGRFQWALFFVLGMALMADGVEVFVVGFVLPSAE
  TDLCIPNSGSGWLGSIVYLGMMVGAFFWGGLADKVGRKQSLLICMSVNGFFAFLSSFVQG
  YGFFLFCRLLSGFGIGGAIPTVFSYFAEVLAREKRGEHLSWLCMFWMIGGIYASAMAWAI
  IPHYGWSFSMGSAYQFHSWRVFVIVCALPCVSSVVALTFMPESPRFLLEVGKHDEAWMIL
  KLIHDTNMRARGQPEKVFTVNKIKTPKQIDELIEIESDTGTWYRRCFVRIRTELYGIWLT
  FMRCFNYPVRDNTIKLTIVWFTLSFGYYGLSVWFPDVIKPLQSDEYALLTRNVERDKYAN
  FTINFTMENQIHTGMEYDNGRFIGVKFKSVTFKDSVFKSCTFEDVTSVNTYFKNCTFIDT
  VFDNTDFEPYKFIDSEFKNCSFFHNKTGCQITFDDDYSAYWIYFVNFLGTLAVLPGNIVS
  ALLMDRIGRLTMLGGSMVLSGISCFFLWFGTSESMMIGMLCLYNGLTISAWNSLDVVTVE
  LYPTDRRATGFGFLNALCKAAAVLGNLIFGSLVSITKSIPILLASTVLVCGGLVGLCLPD
  TRTQVLM
• Function: Plays a role in the control of regulated secretion in neural and endocrine cells, enhancing selectively low-frequency neurotransmission. Positively regulates vesicle fusion by maintaining the readily releasable pool of secretory vesicles; (Microbial infection) Receptor for C.botulinum neurotoxin type A (BoNT/A, botA); the toxin probably binds via extracellular loop 4. Recognition by BoNT/A relies on both protein-protein and protein-N-glycosylation; glycosylation of Asn-559 increases its affinity for BoNT/A. Also serves as a receptor for the closely related C.botulinum neurotoxin type A2; glycosylation is not essential but enhances the interaction ; (Microbial infection) Possible receptor for C.botulinum neurotoxin type D (BoNT/D, botD); note that type D does not usually infect humans.
• KEGG Pathway: ECM-receptor interaction (hsa04512)
• Reactome Pathway:
  Toxicity of botulinum toxin type A (botA) (R-HSA-5250968)
  Toxicity of botulinum toxin type F (botF) (R-HSA-5250981)
  Toxicity of botulinum toxin type D (botD) (R-HSA-5250955)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Huntington disease	DISQPLA4	Strong	Altered Expression	[6]
High blood pressure	DISY2OHH	Limited	Biomarker	[7]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[2]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[7]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bevacizumab	DMSD1UN	Approved	Synaptic vesicle glycoprotein 2C (SV2C) increases the Hypertension ADR of Bevacizumab.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Synaptic vesicle glycoprotein 2C (SV2C).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Synaptic vesicle glycoprotein 2C (SV2C).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Synaptic vesicle glycoprotein 2C (SV2C).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Synaptic vesicle glycoprotein 2C (SV2C).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptic vesicle glycoprotein 2C (SV2C).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Synaptic vesicle glycoprotein 2C (SV2C).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Synaptic vesicle glycoprotein 2C (SV2C).	[12]

References

• [1] Synaptic vesicle protein 2 (SV2) isoforms.Asian Pac J Cancer Prev. 2012;13(10):5063-7. doi: 10.7314/apjcp.2012.13.10.5063.
• [2] Immunochemical analysis of the expression of SV2C in mouse, macaque and human brain.Brain Res. 2019 Jan 1;1702:85-95. doi: 10.1016/j.brainres.2017.12.029. Epub 2017 Dec 21.
• [3] The Synaptic Vesicle Glycoprotein 2: Structure, Function, and Disease Relevance.ACS Chem Neurosci. 2019 Sep 18;10(9):3927-3938. doi: 10.1021/acschemneuro.9b00351. Epub 2019 Aug 23.
• [4] Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. Br J Cancer. 2014 Sep 9;111(6):1241-8. doi: 10.1038/bjc.2014.430. Epub 2014 Aug 12.
• [5] No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy.Epilepsy Res. 2009 Jan;83(1):44-51. doi: 10.1016/j.eplepsyres.2008.09.003. Epub 2008 Oct 31.
• [6] Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C.Neurosci Bull. 2018 Oct;34(5):747-758. doi: 10.1007/s12264-018-0230-x. Epub 2018 Apr 30.
• [7] Synaptic vesicle 2C and its synaptic-related function.Clin Chim Acta. 2017 Sep;472:112-117. doi: 10.1016/j.cca.2017.07.029. Epub 2017 Jul 31.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.