Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7MX5IK)

• DOT Name: Synaptotagmin-like protein 4 (SYTL4)
• Synonyms: Exophilin-2; Granuphilin
• Gene Name: SYTL4
• Related Disease:
  Atrial septal defect
  Autism
  Autism spectrum disorder
  Pervasive developmental disorder
  Retinopathy
• UniProt ID: SYTL4_HUMAN
• PDB ID: 2CSZ; 3FDW; 5X6T
• Pfam ID: PF00168 ; PF02318
• Sequence:
  MSELLDLSFLSEEEKDLILSVLQRDEEVRKADEKRIRRLKNELLEIKRKGAKRGSQHYSD
  RTCARCQESLGRLSPKTNTCRGCNHLVCRDCRIQESNGTWRCKVCAKEIELKKATGDWFY
  DQKVNRFAYRTGSEIIRMSLRHKPAVSKRETVGQSLLHQTQMGDIWPGRKIIQERQKEPS
  VLFEVPKLKSGKSALEAESESLDSFTADSDSTSRRDSLDKSGLFPEWKKMSAPKSQVEKE
  TQPGGQNVVFVDEGEMIFKKNTRKILRPSEYTKSVIDLRPEDVVHESGSLGDRSKSVPGL
  NVDMEEEEEEEDIDHLVKLHRQKLARSSMQSGSSMSTIGSMMSIYSEAGDFGNIFVTGRI
  AFSLKYEQQTQSLVVHVKECHQLAYADEAKKRSNPYVKTYLLPDKSRQGKRKTSIKRDTI
  NPLYDETLRYEIPESLLAQRTLQFSVWHHGRFGRNTFLGEAEIQMDSWKLDKKLDHCLPL
  HGKISAESPTGLPSHKGELVVSLKYIPASKTPVGGDRKKSKGGEGGELQVWIKEAKNLTA
  AKAGGTSDSFVKGYLLPMRNKASKRKTPVMKKTLNPHYNHTFVYNGVRLEDLQHMCLELT
  VWDREPLASNDFLGGVRLGVGTGISNGEVVDWMDSTGEEVSLWQKMRQYPGSWAEGTLQL
  RSSMAKQKLGL
• Function: Modulates exocytosis of dense-core granules and secretion of hormones in the pancreas and the pituitary. Interacts with vesicles containing negatively charged phospholipids in a Ca(2+)-independent manner.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial septal defect	DISJT76B	Strong	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[1]
Retinopathy	DISB4B0F	Limited	X-linked	[2]

12 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 Synaptotagmin-like protein 4 (SYTL4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Synaptotagmin-like protein 4 (SYTL4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Synaptotagmin-like protein 4 (SYTL4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Synaptotagmin-like protein 4 (SYTL4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptotagmin-like protein 4 (SYTL4).	[15]

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 affects the methylation of Synaptotagmin-like protein 4 (SYTL4).	[12]

References

• [1] High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies.Int J Mol Sci. 2019 Jul 9;20(13):3358. doi: 10.3390/ijms20133358.
• [2] 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.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] 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.
• [10] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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.
• [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] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [15] 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.