Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSBUZB4)

• DOT Name: Syntaxin-1A (STX1A)
• Synonyms: Neuron-specific antigen HPC-1
• Gene Name: STX1A
• Related Disease:
  Epilepsy
  Adenoma
  Alzheimer disease
  Astrocytoma
  Attention deficit hyperactivity disorder
  Bacillary dysentery
  Breast cancer
  Breast carcinoma
  Colon carcinoma
  Colorectal carcinoma
  Cystic fibrosis
  Gastric cancer
  Hemolytic-uremic syndrome
  Mental disorder
  Migraine disorder
  Multiple sclerosis
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Advanced cancer
  Autism
  Epithelial ovarian cancer
  Myocardial ischemia
  Ovarian cancer
  Type-1/2 diabetes
  Autism spectrum disorder
  Bladder cancer
  Neoplasm
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: STX1A_HUMAN
• Pfam ID: PF05739 ; PF00804
• Sequence:
  MKDRTQELRTAKDSDDDDDVAVTVDRDRFMDEFFEQVEEIRGFIDKIAENVEEVKRKHSA
  ILASPNPDEKTKEELEELMSDIKKTANKVRSKLKSIEQSIEQEEGLNRSSADLRIRKTQH
  STLSRKFVEVMSEYNATQSDYRERCKGRIQRQLEITGRTTTSEELEDMLESGNPAIFASG
  IIMDSSISKQALSEIETRHSEIIKLENSIRELHDMFMDMAMLVESQGEMIDRIEYNVEHA
  VDYVERAVSDTKKAVKYQSKARRKKIMIIICCVILGIVIASTVGGIFA
• Function: Plays an essential role in hormone and neurotransmitter calcium-dependent exocytosis and endocytosis. Part of the SNARE (Soluble NSF Attachment Receptor) complex composed of SNAP25, STX1A and VAMP2 which mediates the fusion of synaptic vesicles with the presynaptic plasma membrane. STX1A and SNAP25 are localized on the plasma membrane while VAMP2 resides in synaptic vesicles. The pairing of the three SNAREs from the N-terminal SNARE motifs to the C-terminal anchors leads to the formation of the SNARE complex, which brings membranes into close proximity and results in final fusion. Participates in the calcium-dependent regulation of acrosomal exocytosis in sperm. Also plays an important role in the exocytosis of hormones such as insulin or glucagon-like peptide 1 (GLP-1).
• Tissue Specificity: .Highly expressed in embryonic spinal cord and ganglia and in adult cerebellum and cerebral cortex.; [Isoform 2]: Expressed in heart, liver, fat, skeletal muscle, kidney and brain.
• KEGG Pathway:
  S.RE interactions in vesicular transport (hsa04130)
  Sy.ptic vesicle cycle (hsa04721)
  Insulin secretion (hsa04911)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  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)
  Other interleukin signaling (R-HSA-449836)
  Toxicity of botulinum toxin type C (botC) (R-HSA-5250971)
  LGI-ADAM interactions (R-HSA-5682910)
  Neurexins and neuroligins (R-HSA-6794361)
  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)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[5]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Cystic fibrosis	DIS2OK1Q	Strong	GermlineModifyingMutation	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Hemolytic-uremic syndrome	DISSCBGW	Strong	Biomarker	[12]
Mental disorder	DIS3J5R8	Strong	Biomarker	[13]
Migraine disorder	DISFCQTG	Strong	Biomarker	[14]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[17]
Autism	DISV4V1Z	moderate	Altered Expression	[18]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[17]
Myocardial ischemia	DISFTVXF	moderate	Genetic Variation	[19]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[20]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[21]
Bladder cancer	DISUHNM0	Limited	Altered Expression	[22]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[23]
Pervasive developmental disorder	DIS51975	Limited	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[22]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Syntaxin-1A (STX1A).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Syntaxin-1A (STX1A).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Syntaxin-1A (STX1A).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Syntaxin-1A (STX1A).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Syntaxin-1A (STX1A).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Syntaxin-1A (STX1A).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Syntaxin-1A (STX1A).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Syntaxin-1A (STX1A).	[31]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Syntaxin-1A (STX1A).	[33]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Syntaxin-1A (STX1A).	[34]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Syntaxin-1A (STX1A).	[35]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Syntaxin-1A (STX1A).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Syntaxin-1A (STX1A).	[37]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Syntaxin-1A (STX1A).	[25]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Syntaxin-1A (STX1A).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Syntaxin-1A (STX1A).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Syntaxin-1A (STX1A).	[40]

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 Syntaxin-1A (STX1A).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Syntaxin-1A (STX1A).	[41]

References

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• [2] Heterogeneous expression of SNARE proteins SNAP-23, SNAP-25, Syntaxin1 and VAMP in human parathyroid tissue.Mol Cell Endocrinol. 2008 Jun 11;287(1-2):72-80. doi: 10.1016/j.mce.2008.01.028. Epub 2008 Mar 10.
• [3] SNARE Complex Polymorphisms Associate with Alterations of Visual Selective Attention in Alzheimer's Disease.J Alzheimers Dis. 2019;69(1):179-188. doi: 10.3233/JAD-190147.
• [4] Expression of syntaxin 1C, an alternative splice variant of HPC-1/syntaxin 1A, is enhanced by phorbol-ester stimulation in astroglioma: participation of the PKC signaling pathway.FEBS Lett. 2003 Feb 11;536(1-3):209-14. doi: 10.1016/s0014-5793(03)00015-2.
• [5] STX1A gene variations contribute to the susceptibility of children attention-deficit/hyperactivity disorder: a case-control association study.Eur Arch Psychiatry Clin Neurosci. 2019 Sep;269(6):689-699. doi: 10.1007/s00406-019-01010-3. Epub 2019 Apr 11.
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• [9] A conserved role for Syntaxin-1 in pre- and post-commissural midline axonal guidance in fly, chick, and mouse.PLoS Genet. 2018 Jun 18;14(6):e1007432. doi: 10.1371/journal.pgen.1007432. eCollection 2018 Jun.
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• [11] Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.Cell Prolif. 2019 May;52(3):e12607. doi: 10.1111/cpr.12607. Epub 2019 Apr 6.
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• [15] 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.
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• [17] Efficient antiproliferative and antiangiogenic effects on human ovarian cancer growth by gene transfer of attenuated mutants of Shiga-like toxin I.Int J Gynecol Cancer. 2008 Jul-Aug;18(4):677-91. doi: 10.1111/j.1525-1438.2007.01090.x. Epub 2007 Oct 18.
• [18] Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility.Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):454-8. doi: 10.1016/j.pnpbp.2010.11.033. Epub 2010 Nov 29.
• [19] The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease.Medicine (Baltimore). 2019 Jun;98(24):e15846. doi: 10.1097/MD.0000000000015846.
• [20] Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients.Diabetes. 2006 Feb;55(2):435-40. doi: 10.2337/diabetes.55.02.06.db04-1575.
• [21] A part of patients with autism spectrum disorder has haploidy of HPC-1/syntaxin1A gene that possibly causes behavioral disturbance as in experimentally gene ablated mice.Neurosci Lett. 2017 Mar 22;644:5-9. doi: 10.1016/j.neulet.2017.02.052. Epub 2017 Feb 22.
• [22] Increased expression levels of Syntaxin 1A and Synaptobrevin 2/Vesicle-Associated Membrane Protein-2 are associated with the progression of bladder cancer.Genet Mol Biol. 2019 Jan-Mar;42(1):40-47. doi: 10.1590/1678-4685-GMB-2017-0339. Epub 2019 Jan 21.
• [23] New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment.J Biol Chem. 2017 Feb 10;292(6):2203-2216. doi: 10.1074/jbc.M116.769885. Epub 2016 Dec 28.
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• [30] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [31] 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.
• [32] 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.
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• [34] 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.
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• [36] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
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• [38] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [39] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [40] 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.
• [41] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.