Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM34U6Q)

• DOT Name: Anoctamin-3 (ANO3)
• Synonyms: Transmembrane protein 16C
• Gene Name: ANO3
• Related Disease:
  Alzheimer disease
  Bjornstad syndrome
  Cerebellar ataxia
  Dystonia
  Dystonia 24
  Essential tremor
  Late-onset Parkinson disease
  Movement disorder
  Narcolepsy
  Parkinson disease
  Systemic lupus erythematosus
  Asthma
• UniProt ID: ANO3_HUMAN
• Pfam ID: PF16178 ; PF04547
• Sequence:
  MVHHSGSIQSFKQQKGMNISKSEITKETSLKPSRRSLPCLAQSYAYSKSLSQSTSLFQST
  ESESQAPTSITLISTDKAEQVNTEENKNDSVLRCSFADLSDFCLALGKDKDYTDESEHAT
  YDRSRLINDFVIKDKSEFKTKLSKNDMNYIASSGPLFKDGKKRIDYILVYRKTNIQYDKR
  NTFEKNLRAEGLMLEKEPAIASPDIMFIKIHIPWDTLCKYAERLNIRMPFRKKCYYTDGR
  SKSMGRMQTYFRRIKNWMAQNPMVLDKSAFPDLEESDCYTGPFSRARIHHFIINNKDTFF
  SNATRSRIVYHMLERTKYENGISKVGIRKLINNGSYIAAFPPHEGAYKSSQPIKTHGPQN
  NRHLLYERWARWGMWYKHQPLDLIRLYFGEKIGLYFAWLGWYTGMLIPAAIVGLCVFFYG
  LFTMNNSQVSQEICKATEVFMCPLCDKNCSLQRLNDSCIYAKVTYLFDNGGTVFFAIFMA
  IWATVFLEFWKRRRSILTYTWDLIEWEEEEETLRPQFEAKYYKMEIVNPITGKPEPHQPS
  SDKVTRLLVSVSGIFFMISLVITAVFGVVVYRLVVMEQFASFKWNFIKQYWQFATSAAAV
  CINFIIIMLLNLAYEKIAYLLTNLEYPRTESEWENSFALKMFLFQFVNLNSSIFYIAFFL
  GRFVGHPGKYNKLFDRWRLEECHPSGCLIDLCLQMGVIMFLKQIWNNFMELGYPLIQNWW
  SRHKIKRGIHDASIPQWENDWNLQPMNLHGLMDEYLEMVLQFGFTTIFVAAFPLAPLLAL
  LNNIIEIRLDAYKFVTQWRRPLPARATDIGIWLGILEGIGILAVITNAFVIAITSDYIPR
  FVYEYKYGPCANHVEPSENCLKGYVNNSLSFFDLSELGMGKSGYCRYRDYRGPPWSSKPY
  EFTLQYWHILAARLAFIIVFEHLVFGIKSFIAYLIPDVPKGLHDRIRREKYLVQEMMYEA
  ELEHLQQQRRKSGQPVHHEWP
• Function: Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylcholine and galactosylceramide. Seems to act as potassium channel regulator and may inhibit pain signaling; can facilitate KCNT1/Slack channel activity by promoting its full single-channel conductance at very low sodium concentrations and by increasing its sodium sensitivity. Does not exhibit calcium-activated chloride channel (CaCC) activity.
• Tissue Specificity: Highly expressed in the forebrain striatum.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway:
  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
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Bjornstad syndrome	DISO267N	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Dystonia	DISJLFGW	Strong	Genetic Variation	[4]
Dystonia 24	DIS4IYFY	Strong	Autosomal dominant	[5]
Essential tremor	DIS7GBKQ	Strong	Genetic Variation	[6]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[4]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[4]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[8]
Asthma	DISW9QNS	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Anoctamin-3 (ANO3) affects the response to substance of Daunorubicin.	[22]

11 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 Anoctamin-3 (ANO3).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Anoctamin-3 (ANO3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Anoctamin-3 (ANO3).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Anoctamin-3 (ANO3).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Anoctamin-3 (ANO3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Anoctamin-3 (ANO3).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Anoctamin-3 (ANO3).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Anoctamin-3 (ANO3).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Anoctamin-3 (ANO3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Anoctamin-3 (ANO3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Anoctamin-3 (ANO3).	[21]

2 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 increases the methylation of Anoctamin-3 (ANO3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Anoctamin-3 (ANO3).	[19]

References

• [1] Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.Alzheimers Dement. 2018 May;14(5):623-633. doi: 10.1016/j.jalz.2017.11.006. Epub 2017 Dec 20.
• [2] Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls.Mov Disord. 2014 Jan;29(1):143-7. doi: 10.1002/mds.25715. Epub 2013 Oct 22.
• [3] Diagnosis and treatment of pediatric onset isolated dystonia.Eur J Paediatr Neurol. 2018 Mar;22(2):238-244. doi: 10.1016/j.ejpn.2018.01.006. Epub 2018 Jan 17.
• [4] Role of ANO3 mutations in dystonia: A large-scale mutational screening study.Parkinsonism Relat Disord. 2019 May;62:196-200. doi: 10.1016/j.parkreldis.2018.12.030. Epub 2019 Jan 2.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] A step toward essential tremor gene discovery: identification of extreme phenotype and screening of HTRA2 and ANO3.BMC Neurol. 2016 Nov 23;16(1):238. doi: 10.1186/s12883-016-0748-3.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] Pharmacogenetic analysis of belimumab fails to identify robust genetic predictors of efficacy in lupus.Pharmacogenet Genomics. 2019 Aug;29(6):132-135. doi: 10.1097/FPC.0000000000000378.
• [9] The ANO3/MUC15 locus is associated with eczema in families ascertained through asthma.J Allergy Clin Immunol. 2012 Jun;129(6):1547-53.e3. doi: 10.1016/j.jaci.2012.04.010.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] 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.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.