Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTA5KQJ)

• DOT Name: Anoctamin-6 (ANO6)
• Synonyms: Small-conductance calcium-activated nonselective cation channel; SCAN channel; Transmembrane protein 16F
• Gene Name: ANO6
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Ankylosing spondylitis
  Glioblastoma multiforme
  Glioma
  Muscular dystrophy
  Scott syndrome
  Sleep disorder, initiating and maintaining sleep
  Ebola virus infection
  Intellectual disability
  Pancreatic ductal carcinoma
  Secretory diarrhea
• UniProt ID: ANO6_HUMAN
• Pfam ID: PF16178 ; PF04547
• Sequence:
  MKKMSRNVLLQMEEEEDDDDGDIVLENLGQTIVPDLGSLESQHDFRTPEFEEFNGKPDSL
  FFNDGQRRIDFVLVYEDESRKETNKKGTNEKQRRKRQAYESNLICHGLQLEATRSVLDDK
  LVFVKVHAPWEVLCTYAEIMHIKLPLKPNDLKNRSSAFGTLNWFTKVLSVDESIIKPEQE
  FFTAPFEKNRMNDFYIVDRDAFFNPATRSRIVYFILSRVKYQVINNVSKFGINRLVNSGI
  YKAAFPLHDCKFRRQSEDPSCPNERYLLYREWAHPRSIYKKQPLDLIRKYYGEKIGIYFA
  WLGYYTQMLLLAAVVGVACFLYGYLNQDNCTWSKEVCHPDIGGKIIMCPQCDRLCPFWKL
  NITCESSKKLCIFDSFGTLVFAVFMGVWVTLFLEFWKRRQAELEYEWDTVELQQEEQARP
  EYEARCTHVVINEITQEEERIPFTAWGKCIRITLCASAVFFWILLIIASVIGIIVYRLSV
  FIVFSAKLPKNINGTDPIQKYLTPQTATSITASIISFIIIMILNTIYEKVAIMITNFELP
  RTQTDYENSLTMKMFLFQFVNYYSSCFYIAFFKGKFVGYPGDPVYWLGKYRNEECDPGGC
  LLELTTQLTIIMGGKAIWNNIQEVLLPWIMNLIGRFHRVSGSEKITPRWEQDYHLQPMGK
  LGLFYEYLEMIIQFGFVTLFVASFPLAPLLALVNNILEIRVDAWKLTTQFRRLVPEKAQD
  IGAWQPIMQGIAILAVVTNAMIIAFTSDMIPRLVYYWSFSVPPYGDHTSYTMEGYINNTL
  SIFKVADFKNKSKGNPYSDLGNHTTCRYRDFRYPPGHPQEYKHNIYYWHVIAAKLAFIIV
  MEHVIYSVKFFISYAIPDVSKRTKSKIQREKYLTQKLLHENHLKDMTKNMGVIAERMIEA
  VDNNLRPKSE
• Function: Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide. Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes; (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, is activated by spike protein which increases the amplitude of spontaneous Ca(2+) signals and is required for spike-mediated syncytia.
• Tissue Specificity: Expressed in embryonic stem cell, fetal liver, retina, chronic myologenous leukemia and intestinal cancer.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[2]
Scott syndrome	DIS4N4IB	Strong	Autosomal recessive	[4]
Sleep disorder, initiating and maintaining sleep	DISVOIRA	Disputed	Genetic Variation	[5]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[6]
Intellectual disability	DISMBNXP	Limited	Biomarker	[7]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[8]
Secretory diarrhea	DISBX8WG	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Anoctamin-6 (ANO6).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Anoctamin-6 (ANO6).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Anoctamin-6 (ANO6).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Anoctamin-6 (ANO6).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Anoctamin-6 (ANO6).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Anoctamin-6 (ANO6).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Anoctamin-6 (ANO6).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Anoctamin-6 (ANO6).	[17]

1 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 Anoctamin-6 (ANO6).	[15]

References

• [1] ANO6 promotes cell proliferation and invasion in glioma through regulating the ERK signaling pathway.Onco Targets Ther. 2019 Aug 20;12:6721-6731. doi: 10.2147/OTT.S211725. eCollection 2019.
• [2] Physiological roles and diseases of Tmem16/Anoctamin proteins: are they all chloride channels?.Acta Pharmacol Sin. 2011 Jun;32(6):685-92. doi: 10.1038/aps.2011.48.
• [3] Association study of polymorphisms rs4552569 and rs17095830 and the risk of ankylosing spondylitis in a Taiwanese population.PLoS One. 2013;8(1):e52801. doi: 10.1371/journal.pone.0052801. Epub 2013 Jan 4.
• [4] Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010 Dec 9;468(7325):834-8. doi: 10.1038/nature09583. Epub 2010 Nov 24.
• [5] Genome-wide analysis of insomnia disorder.Mol Psychiatry. 2018 Nov;23(11):2238-2250. doi: 10.1038/s41380-018-0033-5. Epub 2018 Mar 8.
• [6] Role of Transmembrane Protein 16F in the Incorporation of Phosphatidylserine Into Budding Ebola Virus Virions.J Infect Dis. 2018 Nov 22;218(suppl_5):S335-S345. doi: 10.1093/infdis/jiy485.
• [7] Haploinsufficiency of ANO6, NELL2 and DBX2 in a boy with intellectual disability and growth delay.Am J Med Genet A. 2015 Aug;167A(8):1890-6. doi: 10.1002/ajmg.a.37079. Epub 2015 Apr 6.
• [8] CCR7 regulates ANO6 to promote migration of pancreatic ductal adenocarcinoma cells via the ERK signaling pathway.Oncol Lett. 2018 Aug;16(2):2599-2605. doi: 10.3892/ol.2018.8962. Epub 2018 Jun 13.
• [9] Anoctamin 6 Contributes to Cl- Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea: AN ESSENTIAL ROLE FOR PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE (PIP2) SIGNALING IN CHOLERA.J Biol Chem. 2016 Dec 23;291(52):26816-26836. doi: 10.1074/jbc.M116.719823. Epub 2016 Oct 31.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] 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.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 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.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.