Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSZLI64)

• DOT Name: Septin-8 (SEPTIN8)
• Gene Name: SEPTIN8
• Related Disease:
  Alzheimer disease
  Asthma
  Ebola virus infection
• UniProt ID: SEPT8_HUMAN
• PDB ID: 6UPR; 6WSM
• Pfam ID: PF00735
• Sequence:
  MAATDLERFSNAEPEPRSLSLGGHVGFDSLPDQLVSKSVTQGFSFNILCVGETGIGKSTL
  MNTLFNTTFETEEASHHEACVRLRPQTYDLQESNVQLKLTIVDAVGFGDQINKDESYRPI
  VDYIDAQFENYLQEELKIRRSLFDYHDTRIHVCLYFITPTGHSLKSLDLVTMKKLDSKVN
  IIPIIAKADTISKSELHKFKIKIMGELVSNGVQIYQFPTDDEAVAEINAVMNAHLPFAVV
  GSTEEVKVGNKLVRARQYPWGVVQVENENHCDFVKLREMLIRVNMEDLREQTHSRHYELY
  RRCKLEEMGFQDSDGDSQPFSLQETYEAKRKEFLSELQRKEEEMRQMFVNKVKETELELK
  EKERELHEKFEHLKRVHQEEKRKVEEKRRELEEETNAFNRRKAAVEALQSQALHATSQQP
  LRKDKDKKNRSDIGAHQPGMSLSSSKVMMTKASVEPLNCSSWWPAIQCCSCLVRDATWRE
  GFL
• Function: Filament-forming cytoskeletal GTPase. May play a role in platelet secretion. Seems to participate in the process of SNARE complex formation in synaptic vesicles; [Isoform 4]: Stabilizes BACE1 protein levels and promotes the sorting and accumulation of BACE1 to the recycling or endosomal compartments, modulating the beta-amyloidogenic processing of APP.
• Tissue Specificity: Widely expressed, including in brain, heart and platelets; most abundant in aorta. Isoform 2 is expressed at low levels in specific brain areas, such as occipital pole, frontal lobe, temporal lobe and putamen. Isoform 1 and 3 are highly expressed in specific brain areas, such as occipital pole, frontal lobe, temporal lobe and putamen. Isoform 2 is highly expressed in prostate, testis and ovary. Isoform 1 and isoform 3 are expressed at low levels in prostate, testis and ovary.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Asthma	DISW9QNS	Limited	Genetic Variation	[2]
Ebola virus infection	DISJAVM1	Limited	Genetic Variation	[3]

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 Septin-8 (SEPTIN8).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Septin-8 (SEPTIN8).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Septin-8 (SEPTIN8).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Septin-8 (SEPTIN8).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Septin-8 (SEPTIN8).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Septin-8 (SEPTIN8).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Septin-8 (SEPTIN8).	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Septin-8 (SEPTIN8).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Septin-8 (SEPTIN8).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Septin-8 (SEPTIN8).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Septin-8 (SEPTIN8).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Septin-8 (SEPTIN8).	[17]

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 Septin-8 (SEPTIN8).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Septin-8 (SEPTIN8).	[14]

References

• [1] SEPT8 modulates -amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1.J Cell Sci. 2016 Jun 1;129(11):2224-38. doi: 10.1242/jcs.185215. Epub 2016 Apr 15.
• [2] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [3] Prevalence of infection among asymptomatic and paucisymptomatic contact persons exposed to Ebola virus in Guinea: a retrospective, cross-sectional observational study.Lancet Infect Dis. 2019 Mar;19(3):308-316. doi: 10.1016/S1473-3099(18)30649-2. Epub 2019 Feb 11.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.