Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQNOHR8)

• DOT Name: Double-stranded RNA-specific adenosine deaminase (ADAR)
• Synonyms: DRADA; EC 3.5.4.37; 136 kDa double-stranded RNA-binding protein; p136; Interferon-inducible protein 4; IFI-4; K88DSRBP
• Gene Name: ADAR
• Related Disease:
  Aicardi-Goutieres syndrome
  Aicardi-Goutieres syndrome 6
  Dyschromatosis symmetrica hereditaria
  Neoplasm
  Acute myelogenous leukaemia
  Advanced cancer
  Aicardi-Goutieres syndrome 1
  Aicardi-Goutieres syndrome 2
  Amyotrophic lateral sclerosis
  Autoimmune disease
  Breast cancer
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Chronic hepatitis B virus infection
  Colorectal carcinoma
  Epithelial ovarian cancer
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatitis D virus infection
  Hepatocellular carcinoma
  Infantile bilateral striatal necrosis
  Leukemia
  Lung adenocarcinoma
  Lung carcinoma
  Measles
  Plasma cell myeloma
  Prostate carcinoma
  Pseudo-TORCH syndrome
  Rheumatoid arthritis
  Squamous cell carcinoma
  Stomach cancer
  Systemic lupus erythematosus
  Adenocarcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Influenza
  Liver cancer
  Movement disorder
  Familial infantile bilateral striatal necrosis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Breast carcinoma
  Breast neoplasm
  Coronary atherosclerosis
  Coronary heart disease
  Dystonia
  Leigh syndrome
  Lung cancer
  Melanoma
  Metastatic melanoma
  Skin disease
• UniProt ID: DSRAD_HUMAN
• PDB ID: 1QBJ; 1QGP; 1XMK; 2ACJ; 2GXB; 2L54; 2MDR; 3F21; 3F22; 3F23; 3IRQ; 3IRR; 5ZU1; 5ZUO; 5ZUP; 7C0I; 7ZJ1; 7ZLQ; 8GBC; 8GBD
• EC Number: 3.5.4.37
• Pfam ID: PF02137 ; PF00035 ; PF02295
• Sequence:
  MNPRQGYSLSGYYTHPFQGYEHRQLRYQQPGPGSSPSSFLLKQIEFLKGQLPEAPVIGKQ
  TPSLPPSLPGLRPRFPVLLASSTRGRQVDIRGVPRGVHLRSQGLQRGFQHPSPRGRSLPQ
  RGVDCLSSHFQELSIYQDQEQRILKFLEELGEGKATTAHDLSGKLGTPKKEINRVLYSLA
  KKGKLQKEAGTPPLWKIAVSTQAWNQHSGVVRPDGHSQGAPNSDPSLEPEDRNSTSVSED
  LLEPFIAVSAQAWNQHSGVVRPDSHSQGSPNSDPGLEPEDSNSTSALEDPLEFLDMAEIK
  EKICDYLFNVSDSSALNLAKNIGLTKARDINAVLIDMERQGDVYRQGTTPPIWHLTDKKR
  ERMQIKRNTNSVPETAPAAIPETKRNAEFLTCNIPTSNASNNMVTTEKVENGQEPVIKLE
  NRQEARPEPARLKPPVHYNGPSKAGYVDFENGQWATDDIPDDLNSIRAAPGEFRAIMEMP
  SFYSHGLPRCSPYKKLTECQLKNPISGLLEYAQFASQTCEFNMIEQSGPPHEPRFKFQVV
  INGREFPPAEAGSKKVAKQDAAMKAMTILLEEAKAKDSGKSEESSHYSTEKESEKTAESQ
  TPTPSATSFFSGKSPVTTLLECMHKLGNSCEFRLLSKEGPAHEPKFQYCVAVGAQTFPSV
  SAPSKKVAKQMAAEEAMKALHGEATNSMASDNQPEGMISESLDNLESMMPNKVRKIGELV
  RYLNTNPVGGLLEYARSHGFAAEFKLVDQSGPPHEPKFVYQAKVGGRWFPAVCAHSKKQG
  KQEAADAALRVLIGENEKAERMGFTEVTPVTGASLRRTMLLLSRSPEAQPKTLPLTGSTF
  HDQIAMLSHRCFNTLTNSFQPSLLGRKILAAIIMKKDSEDMGVVVSLGTGNRCVKGDSLS
  LKGETVNDCHAEIISRRGFIRFLYSELMKYNSQTAKDSIFEPAKGGEKLQIKKTVSFHLY
  ISTAPCGDGALFDKSCSDRAMESTESRHYPVFENPKQGKLRTKVENGEGTIPVESSDIVP
  TWDGIRLGERLRTMSCSDKILRWNVLGLQGALLTHFLQPIYLKSVTLGYLFSQGHLTRAI
  CCRVTRDGSAFEDGLRHPFIVNHPKVGRVSIYDSKRQSGKTKETSVNWCLADGYDLEILD
  GTRGTVDGPRNELSRVSKKNIFLLFKKLCSFRYRRDLLRLSYGEAKKAARDYETAKNYFK
  KGLKDMGYGNWISKPQEEKNFYLCPV
• 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 since the translational machinery read the inosine as a guanosine; 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 serotonin (HTR2C) and GABA receptor (GABRA3). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1. Its viral RNA substrates include: hepatitis C virus (HCV), vesicular stomatitis virus (VSV), measles virus (MV), hepatitis delta virus (HDV), and human immunodeficiency virus type 1 (HIV-1). Exhibits either a proviral (HDV, MV, VSV and HIV-1) or an antiviral effect (HCV) and this can be editing-dependent (HDV and HCV), editing-independent (VSV and MV) or both (HIV-1). Impairs HCV replication via RNA editing at multiple sites. Enhances the replication of MV, VSV and HIV-1 through an editing-independent mechanism via suppression of EIF2AK2/PKR activation and function. Stimulates both the release and infectivity of HIV-1 viral particles by an editing-dependent mechanism where it associates with viral RNAs and edits adenosines in the 5'UTR and the Rev and Tat coding sequence. Can enhance viral replication of HDV via A-to-I editing at a site designated as amber/W, thereby changing an UAG amber stop codon to an UIG tryptophan (W) codon that permits synthesis of the large delta antigen (L-HDAg) which has a key role in the assembly of viral particles. However, high levels of ADAR1 inhibit HDV replication.
• Tissue Specificity: Ubiquitously expressed, highest levels were found in brain and lung . Isoform 5 is expressed at higher levels in astrocytomas as compared to normal brain tissue and expression increases strikingly with the severity of the tumor, being higher in the most aggressive tumors.
• KEGG Pathway:
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Formation of editosomes by ADAR proteins (R-HSA-77042)
  Interferon alpha/beta signaling (R-HSA-909733)
  PKR-mediated signaling (R-HSA-9833482)
  C6 deamination of adenosine (R-HSA-75102)

Molecular Interaction Atlas (MIA) of This DOT

51 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome	DIS1NH4X	Definitive	Autosomal recessive	[1]
Aicardi-Goutieres syndrome 6	DIS9TLMY	Definitive	Autosomal recessive	[2]
Dyschromatosis symmetrica hereditaria	DIS9HI9T	Definitive	Autosomal dominant	[3]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Aicardi-Goutieres syndrome 1	DISPAXC2	Strong	Biomarker	[7]
Aicardi-Goutieres syndrome 2	DISOL1R1	Strong	Biomarker	[7]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[8]
Autoimmune disease	DISORMTM	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[11]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[12]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[12]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[14]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[15]
Gastric cancer	DISXGOUK	Strong	Biomarker	[16]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[11]
Glioma	DIS5RPEH	Strong	Genetic Variation	[11]
Hepatitis D virus infection	DISESSLZ	Strong	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
Infantile bilateral striatal necrosis	DIST0SXY	Strong	GermlineCausalMutation	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[19]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[20]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[21]
Measles	DISXSUID	Strong	Biomarker	[22]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[11]
Pseudo-TORCH syndrome	DISM9N8Y	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[25]
Stomach cancer	DISKIJSX	Strong	Biomarker	[16]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[26]
Adenocarcinoma	DIS3IHTY	moderate	Biomarker	[27]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[10]
Influenza	DIS3PNU3	moderate	Biomarker	[28]
Liver cancer	DISDE4BI	moderate	Altered Expression	[10]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[29]
Familial infantile bilateral striatal necrosis	DISTMX8T	Supportive	Autosomal dominant	[2]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[30]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[31]
Coronary atherosclerosis	DISKNDYU	Limited	Altered Expression	[32]
Coronary heart disease	DIS5OIP1	Limited	Altered Expression	[32]
Dystonia	DISJLFGW	Limited	Biomarker	[33]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[1]
Lung cancer	DISCM4YA	Limited	Biomarker	[34]
Melanoma	DIS1RRCY	Limited	Altered Expression	[35]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[35]
Skin disease	DISDW8R6	Limited	Genetic Variation	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Double-stranded RNA-specific adenosine deaminase (ADAR) decreases the response to substance of Methotrexate.	[31]

9 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 Double-stranded RNA-specific adenosine deaminase (ADAR).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[40]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[41]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[43]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Double-stranded RNA-specific adenosine deaminase (ADAR).	[48]

3 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 affects the methylation of Double-stranded RNA-specific adenosine deaminase (ADAR).	[45]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Double-stranded RNA-specific adenosine deaminase (ADAR).	[46]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Double-stranded RNA-specific adenosine deaminase (ADAR).	[47]

References

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• [17] The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-alpha-stimulated host cells.J Viral Hepat. 2006 Mar;13(3):150-7. doi: 10.1111/j.1365-2893.2005.00663.x.
• [18] ADAR1 p110 Enhances Adhesion of Tumor Cells to Extracellular Matrix in Hepatocellular Carcinoma via Up-Regulating ITGA2 Expression.Med Sci Monit. 2019 Feb 24;25:1469-1479. doi: 10.12659/MSM.911944.
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