Details of Drug Off-Target (DOT)

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

• DOT Name: Double-stranded RNA-specific editase 1 (ADARB1)
• Synonyms: EC 3.5.4.37; RNA-editing deaminase 1; RNA-editing enzyme 1; dsRNA adenosine deaminase
• Gene Name: ADARB1
• Related Disease:
  Frontotemporal dementia
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Anaplastic large cell lymphoma
  Autism
  Behcet disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Congenital heart disease
  Endometrial cancer
  Endometrial carcinoma
  Epilepsy
  Esophageal squamous cell carcinoma
  Fragile X syndrome
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Liver cirrhosis
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Malignant soft tissue neoplasm
  Myopathy
  Neoplasm
  Neuralgia
  Neurodevelopmental disorder with hypotonia, microcephaly, and seizures
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Polycystic ovarian syndrome
  Psychotic disorder
  Sarcoma
  Schizophrenia
  Stomach cancer
  Systemic lupus erythematosus
  Hirschsprung disease
  Adult glioblastoma
  Astrocytoma
  Mental disorder
  Migraine disorder
  Mood disorder
  Obesity
  Rett syndrome
• UniProt ID: RED1_HUMAN
• PDB ID: 1ZY7; 5ED1; 5ED2; 5HP2; 5HP3; 6D06; 6VFF; 7KFN; 8E0F; 8E4X
• EC Number: 3.5.4.37
• Pfam ID: PF02137 ; PF00035
• Sequence:
  MDIEDEENMSSSSTDVKENRNLDNVSPKDGSTPGPGEGSQLSNGGGGGPGRKRPLEEGSN
  GHSKYRLKKRRKTPGPVLPKNALMQLNEIKPGLQYTLLSQTGPVHAPLFVMSVEVNGQVF
  EGSGPTKKKAKLHAAEKALRSFVQFPNASEAHLAMGRTLSVNTDFTSDQADFPDTLFNGF
  ETPDKAEPPFYVGSNGDDSFSSSGDLSLSASPVPASLAQPPLPVLPPFPPPSGKNPVMIL
  NELRPGLKYDFLSESGESHAKSFVMSVVVDGQFFEGSGRNKKLAKARAAQSALAAIFNLH
  LDQTPSRQPIPSEGLQLHLPQVLADAVSRLVLGKFGDLTDNFSSPHARRKVLAGVVMTTG
  TDVKDAKVISVSTGTKCINGEYMSDRGLALNDCHAEIISRRSLLRFLYTQLELYLNNKDD
  QKRSIFQKSERGGFRLKENVQFHLYISTSPCGDARIFSPHEPILEGSRSYTQAGVQWCNH
  GSLQPRPPGLLSDPSTSTFQGAGTTEPADRHPNRKARGQLRTKIESGEGTIPVRSNASIQ
  TWDGVLQGERLLTMSCSDKIARWNVVGIQGSLLSIFVEPIYFSSIILGSLYHGDHLSRAM
  YQRISNIEDLPPLYTLNKPLLSGISNAEARQPGKAPNFSVNWTVGDSAIEVINATTGKDE
  LGRASRLCKHALYCRWMRVHGKVPSHLLRSKITKPNVYHESKLAAKEYQAAKARLFTAFI
  KAGLGAWVEKPTEQDQFSLTP
• Function: Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2 and GRIK2) and serotonin (HTR2C), GABA receptor (GABRA3) and potassium voltage-gated channel (KCNA1). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alter their functional activities. Edits GRIA2 at both the Q/R and R/G sites efficiently but converts the adenosine in hotspot1 much less efficiently. Can exert a proviral effect towards human immunodeficiency virus type 1 (HIV-1) and enhances its replication via both an editing-dependent and editing-independent mechanism. The former involves editing of adenosines in the 5'UTR while the latter occurs via suppression of EIF2AK2/PKR activation and function. Can inhibit cell proliferation and migration and can stimulate exocytosis; [Isoform 1]: Has a lower catalytic activity than isoform 2; [Isoform 2]: Has a higher catalytic activity than isoform 1.
• Tissue Specificity: Highly expressed in brain and heart and at lower levels in placenta. Fair expression in lung, liver and kidney. Detected in brain, heart, kidney, lung and liver (at protein level).; [Isoform 5]: Highly expressed in hippocampus and colon. Expressed in pediatric astrocytomas and the protein has a decreased RNA-editing activity. The decrease in RNA editing correlates with the grade of malignancy of the tumors, with the high grade tumors showing lower editing is seen.
• Reactome Pathway:
  Formation of editosomes by ADAR proteins (R-HSA-77042)
  C6 deamination of adenosine (R-HSA-75102)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia	DISKYHXL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Altered Expression	[5]
Behcet disease	DISSYMBS	Strong	Altered Expression	[6]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[11]
Endometrial cancer	DISW0LMR	Strong	Posttranslational Modification	[12]
Endometrial carcinoma	DISXR5CY	Strong	Posttranslational Modification	[12]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[13]
Fragile X syndrome	DISE8W3A	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[15]
Glioma	DIS5RPEH	Strong	Altered Expression	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
Liver cancer	DISDE4BI	Strong	Biomarker	[18]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[19]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[9]
Myopathy	DISOWG27	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Neuralgia	DISWO58J	Strong	Biomarker	[21]
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures	DISAFLGR	Strong	Autosomal recessive	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[24]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[25]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[26]
Sarcoma	DISZDG3U	Strong	Altered Expression	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[26]
Stomach cancer	DISKIJSX	Strong	Biomarker	[14]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[27]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[28]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[15]
Astrocytoma	DISL3V18	Limited	Altered Expression	[5]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[29]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[30]
Mood disorder	DISLVMWO	Limited	Biomarker	[26]
Obesity	DIS47Y1K	Limited	Biomarker	[31]
Rett syndrome	DISGG5UV	Limited	Genetic Variation	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Double-stranded RNA-specific editase 1 (ADARB1) affects the response to substance of Mitoxantrone.	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Double-stranded RNA-specific editase 1 (ADARB1).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Double-stranded RNA-specific editase 1 (ADARB1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Double-stranded RNA-specific editase 1 (ADARB1).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[37]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[44]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Double-stranded RNA-specific editase 1 (ADARB1).	[45]

References

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• [3] Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer's disease.Neurobiol Aging. 2014 Aug;35(8):1785-91. doi: 10.1016/j.neurobiolaging.2014.02.018. Epub 2014 Mar 1.
• [4] CD26, together with cell surface adenosine deaminase, is selectively expressed on ALK-positive, but not on ALK-negative, anaplastic large cell lymphoma and Hodgkin's lymphoma.Leuk Lymphoma. 2006 Oct;47(10):2181-8. doi: 10.1080/10428190600773396.
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• [6] Serum and erythrocyte adenosine deaminase activities in patients with Behet's disease.Int J Dermatol. 2006 Sep;45(9):1053-6. doi: 10.1111/j.1365-4632.2006.02892.x.
• [7] Altered adenosine-to-inosine RNA editing in human cancer.Genome Res. 2007 Nov;17(11):1586-95. doi: 10.1101/gr.6493107. Epub 2007 Oct 1.
• [8] RNA-editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA.FEBS Lett. 2017 Sep;591(18):2890-2904. doi: 10.1002/1873-3468.12795. Epub 2017 Aug 30.
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• [10] The Secretion of miR-200s by a PKC/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer.Cell Rep. 2018 Apr 24;23(4):1178-1191. doi: 10.1016/j.celrep.2018.03.118.
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• [16] Aberrant alternative splicing pattern of ADAR2 downregulates adenosine-to-inosine editing in glioma.Oncol Rep. 2015 Jun;33(6):2845-52. doi: 10.3892/or.2015.3907. Epub 2015 Apr 8.
• [17] A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma.Gut. 2014 May;63(5):832-43. doi: 10.1136/gutjnl-2012-304037. Epub 2013 Jun 13.
• [18] ADAR2-mediated editing of miR-214 and miR-122 precursor and antisense RNA transcripts in liver cancers.PLoS One. 2013 Dec 27;8(12):e81922. doi: 10.1371/journal.pone.0081922. eCollection 2013.
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• [20] Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma.J Biol Chem. 2017 Mar 10;292(10):4326-4335. doi: 10.1074/jbc.M117.779868. Epub 2017 Feb 6.
• [21] RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.FASEB J. 2017 May;31(5):1847-1855. doi: 10.1096/fj.201600950R. Epub 2017 Jan 26.
• [22] Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy. J Med Genet. 2021 Jul;58(7):495-504. doi: 10.1136/jmedgenet-2020-107048. Epub 2020 Jul 27.
• [23] Pilot genome-wide association study identifying novel risk loci for type 2 diabetes in a Maya population.Gene. 2018 Nov 30;677:324-331. doi: 10.1016/j.gene.2018.08.041. Epub 2018 Aug 18.
• [24] Identification of novel deregulated RNA metabolism-related genes in non-small cell lung cancer.PLoS One. 2012;7(8):e42086. doi: 10.1371/journal.pone.0042086. Epub 2012 Aug 2.
• [25] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
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• [27] Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes.Immunology. 2007 Jul;121(3):359-69. doi: 10.1111/j.1365-2567.2007.02582.x. Epub 2007 Mar 22.
• [28] Lipopolysaccharide enhances ADAR2 which drives Hirschsprung's disease by impairing miR-142-3p biogenesis.J Cell Mol Med. 2018 Sep;22(9):4045-4055. doi: 10.1111/jcmm.13652. Epub 2018 Jun 29.
• [29] Joint effect of ADARB1 gene, HTR2C gene and stressful life events on suicide attempt risk in patients with major psychiatric disorders.World J Biol Psychiatry. 2015 Jun;16(4):261-71. doi: 10.3109/15622975.2014.1000374. Epub 2015 Mar 2.
• [30] Case-control study of ADARB1 and ADARB2 gene variants in migraine.J Headache Pain. 2015;16:511. doi: 10.1186/s10194-015-0511-y. Epub 2015 Apr 3.
• [31] Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2.J Biol Chem. 2007 Aug 3;282(31):22448-59. doi: 10.1074/jbc.M700265200. Epub 2007 Jun 12.
• [32] Site-directed RNA repair of endogenous Mecp2 RNA in neurons.Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114. Epub 2017 Oct 16.
• [33] 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.
• [34] 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.
• [35] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [38] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [39] 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.
• [40] 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.
• [41] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [42] 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.
• [43] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [44] 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.
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