Details of Drug Off-Target (DOT)

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

• DOT Name: Syntaxin-8 (STX8)
• Gene Name: STX8
• Related Disease:
  Non-insulin dependent diabetes
  Type-1 diabetes
  Alzheimer disease
  Obesity
  Lysosomal storage disease
• UniProt ID: STX8_HUMAN
• Pfam ID: PF05739
• Sequence:
  MAPDPWFSTYDSTCQIAQEIAEKIQQRNQYERKGEKAPKLTVTIRALLQNLKEKIALLKD
  LLLRAVSTHQITQLEGDRRQNLLDDLVTRERLLLASFKNEGAEPDLIRSSLMSEEAKRGA
  PNPWLFEEPEETRGLGFDEIRQQQQKIIQEQDAGLDALSSIISRQKQMGQEIGNELDEQN
  EIIDDLANLVENTDEKLRNETRRVNMVDRKSASCGMIMVILLLLVAIVVVAVWPTN
• Function: Vesicle trafficking protein that functions in the early secretory pathway, possibly by mediating retrograde transport from cis-Golgi membranes to the ER.
• Tissue Specificity: Highly expressed in heart. Also found in brain, kidney, liver, lung, placenta, skeletal muscle, spleen and pancreas.
• KEGG Pathway: S.RE interactions in vesicular transport (hsa04130)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]
Lysosomal storage disease	DIS6QM6U	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Syntaxin-8 (STX8).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Syntaxin-8 (STX8).	[15]

10 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-8 (STX8).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Syntaxin-8 (STX8).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Syntaxin-8 (STX8).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Syntaxin-8 (STX8).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Syntaxin-8 (STX8).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Syntaxin-8 (STX8).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Syntaxin-8 (STX8).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Syntaxin-8 (STX8).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Syntaxin-8 (STX8).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Syntaxin-8 (STX8).	[17]

References

• [1] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [2] The dietary education trial in carbohydrate counting (DIET-CARB Study): study protocol for a randomised, parallel, open-label, intervention study comparing different approaches to dietary self-management in patients with type 1 diabetes.BMJ Open. 2019 Sep 3;9(9):e029859. doi: 10.1136/bmjopen-2019-029859.
• [3] Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease.J Neurosci Res. 2004 Mar 1;75(5):698-703. doi: 10.1002/jnr.20028.
• [4] Expression of syntaxin 8 in visceral adipose tissue is increased in obese patients with type 2 diabetes and related to markers of insulin resistance and inflammation.Arch Med Res. 2015 Jan;46(1):47-53. doi: 10.1016/j.arcmed.2014.12.003. Epub 2014 Dec 15.
• [5] Homologous modeling of the lysosomal protective protein/carboxypeptidase L: structural and functional implications of mutations identified in galactosialidosis patients.Proteins. 1994 Jan;18(1):81-93. doi: 10.1002/prot.340180110.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [10] 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.
• [11] 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.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] 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.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.