Details of Drug Off-Target (DOT)

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

• DOT Name: Synaptotagmin-11 (SYT11)
• Synonyms: Synaptotagmin XI; SytXI
• Gene Name: SYT11
• Related Disease:
  Multiple sclerosis
  Non-insulin dependent diabetes
  Schizophrenia
• UniProt ID: SYT11_HUMAN
• Pfam ID: PF00168
• Sequence:
  MAEITNIRPSFDVSPVVAGLIGASVLVVCVSVTVFVWSCCHQQAEKKQKNPPYKFIHMLK
  GISIYPETLSNKKKIIKVRRDKDGPGREGGRRNLLVDAAEAGLLSRDKDPRGPSSGSCID
  QLPIKMDYGEELRSPITSLTPGESKTTSPSSPEEDVMLGSLTFSVDYNFPKKALVVTIQE
  AHGLPVMDDQTQGSDPYIKMTILPDKRHRVKTRVLRKTLDPVFDETFTFYGIPYSQLQDL
  VLHFLVLSFDRFSRDDVIGEVMVPLAGVDPSTGKVQLTRDIIKRNIQKCISRGELQVSLS
  YQPVAQRMTVVVLKARHLPKMDITGLSGNPYVKVNVYYGRKRIAKKKTHVKKCTLNPIFN
  ESFIYDIPTDLLPDISIEFLVIDFDRTTKNEVVGRLILGAHSVTASGAEHWREVCESPRK
  PVAKWHSLSEY
• Function: Synaptotagmin family member involved in vesicular and membrane trafficking which does not bind Ca(2+). Inhibits clathrin-mediated and bulk endocytosis, functions to ensure precision in vesicle retrieval. Plays an important role in dopamine transmission by regulating endocytosis and the vesicle-recycling process. Essential component of a neuronal vesicular trafficking pathway that differs from the synaptic vesicle trafficking pathway but is crucial for development and synaptic plasticity. In macrophages and microglia, inhibits the conventional cytokine secretion, of at least IL6 and TNF, and phagocytosis. In astrocytes, regulates lysosome exocytosis, mechanism required for the repair of injured astrocyte cell membrane. Required for the ATP13A2-mediated regulation of the autophagy-lysosome pathway.
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[1]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[2]
Schizophrenia	DISSRV2N	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Synaptotagmin-11 (SYT11).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Synaptotagmin-11 (SYT11).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Synaptotagmin-11 (SYT11).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Synaptotagmin-11 (SYT11).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Synaptotagmin-11 (SYT11).	[8]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Synaptotagmin-11 (SYT11).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Synaptotagmin-11 (SYT11).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Synaptotagmin-11 (SYT11).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Synaptotagmin-11 (SYT11).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Synaptotagmin-11 (SYT11).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Synaptotagmin-11 (SYT11).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Synaptotagmin-11 (SYT11).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Synaptotagmin-11 (SYT11).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Synaptotagmin-11 (SYT11).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Synaptotagmin-11 (SYT11).	[11]

References

• [1] Novel SNARE Complex Polymorphisms Associated with Multiple Sclerosis: Signs of Synaptopathy in Multiple Sclerosis.Balkan Med J. 2019 May 10;36(3):174-178. doi: 10.4274/balkanmedj.galenos.2018.2017.1034. Epub 2018 Dec 24.
• [2] Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes.Mol Cell Endocrinol. 2012 Nov 25;364(1-2):36-45. doi: 10.1016/j.mce.2012.08.009. Epub 2012 Aug 23.
• [3] Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity.Genes Dev. 2019 Mar 1;33(5-6):365-376. doi: 10.1101/gad.320077.118. Epub 2019 Feb 26.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [15] 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.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.