Information on EC 3.5.4.37 - double-stranded RNA adenine deaminase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.5.4.37
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RECOMMENDED NAME
GeneOntology No.
double-stranded RNA adenine deaminase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
adenine in double-stranded RNA + H2O = hypoxanthine in double-stranded RNA + NH3
show the reaction diagram
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SYSTEMATIC NAME
IUBMB Comments
double-stranded RNA(adenine) aminohydrolase
This eukaryotic enzyme is involved in RNA editing. It destabilizes double-stranded RNA through conversion of adenosine to inosine. Inositol hexakisphosphate is required for activity [4].
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
8-azaadenine in double-stranded RNA + H2O
8-azahypoxanthine in double-stranded RNA + NH3
show the reaction diagram
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8-aza substitution at adenosine in various RNA substrates accelerates the rate of deamination at these sites by ADAR2 (2.8-17-fold). The magnitude of this effect depends on the RNA structural context of the reacting nucleotide
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?
adenine in double-stranded RNA + H2O
hypoxanthine in double-stranded RNA + NH3
show the reaction diagram
adenosine in double-stranded RNA + H2O
hypoxanthine in double-stranded RNA + NH3
show the reaction diagram
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although codon editing is important, it represents only a small fraction of the editing events in the transcriptome. Editing sites in non-coding regions of RNA are more prevalent. Introns and untranslated regions of mRNA are the primary non-coding targets, but editing also occurs in small RNAs, such as miRNAs. functions in the regulation of a variety of post-transcriptional processes. Inosine has different base-pairing properties from adenosine, and thus, editing alters RNA structure, coding potential and splicing patterns. Function primarily in proteome diversification, especially in the nervous system. Inosine is recognized as guanosine by the translation and splicing machineries, and thus, ADARs can alter the protein-coding information of an mRNA. In addition, because inosine prefers to pair with cytidine, ADARs destabilize dsRNA by changing AU base-pairs to IU mismatches, or increase its stability by changing AC mismatches to IC base-pairs
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?
N6-methyladenine in double-stranded RNA + H2O
N6-methylhypoxanthine in double-stranded RNA + NH3
show the reaction diagram
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slow substrate for ADAR2, 2% of the rate compared to that of adenosine
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
adenine in double-stranded RNA + H2O
hypoxanthine in double-stranded RNA + NH3
show the reaction diagram
adenosine in double-stranded RNA + H2O
hypoxanthine in double-stranded RNA + NH3
show the reaction diagram
-
although codon editing is important, it represents only a small fraction of the editing events in the transcriptome. Editing sites in non-coding regions of RNA are more prevalent. Introns and untranslated regions of mRNA are the primary non-coding targets, but editing also occurs in small RNAs, such as miRNAs. functions in the regulation of a variety of post-transcriptional processes. Inosine has different base-pairing properties from adenosine, and thus, editing alters RNA structure, coding potential and splicing patterns. Function primarily in proteome diversification, especially in the nervous system. Inosine is recognized as guanosine by the translation and splicing machineries, and thus, ADARs can alter the protein-coding information of an mRNA. In addition, because inosine prefers to pair with cytidine, ADARs destabilize dsRNA by changing AU base-pairs to IU mismatches, or increase its stability by changing AC mismatches to IC base-pairs
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?
additional information
?
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P55265
overexpression of p150 ADAR1 has no significant effect on the yield of vesicular stomatitis virus. reduction of p110 and p150 ADAR1 proteins to less than 10% to 15% of parental levels (ADAR1-deficient) has no significant effect on growth of Vesicular Stomatitis Virus in the absence of interferon treatment. The level of phosphorylated protein kinase PKR is increased in ADAR1-deficient cells compared to ADAR1-sufficient cells following IFN treatment, regardless of viral infection. ADAR1 suppresses activation of protein kinase PKR and inhibition of growth of Vesicular Stomatitis Virus in response to interferon treatment
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Inositol hexakisphosphate
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is buried within the enzyme core, contributing to the protein fold. Inositol hexakisphosphate is required for activity. Amino acids that coordinate inositol hexakisphosphate in the crystal structure are conserved in some adenosine deaminases that act on tRNA
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zinc
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the structure reveals zinc in the active site
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
8-azanebularine
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ammonium acetate
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0.4 M, complete inhibition
Basic proteins
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histones and lysozyme, 0.5 mg/ml, complete inhibition
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Double-stranded RNA
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excess of substrate inhibits
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heparin
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0.5 mg/ml, complete inhibition
iodoacetate
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10 mM, complete inhibition
KCl
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0.2 M, complete inhibition
N-ethylmaleimide
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10 mM, complete inhibition
NaCl
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0.2 M, complete inhibition
potassium phosphate
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Sodium phosphate
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spermidine
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0.5 mg/ml, complete inhibition
TLCK
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1 mM, complete inhibition
ZnCl2
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1 mM, complete inhibition
additional information
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no inhibition: DNA (salmon sperm, 0.3 mg/ml), RNA (torula yeast, 0.3 mg/ml), acidic proteins (bovine serum albumin and casein, 2.0 mg/ml), polyglutamic acid (2.0 mg/ml), glutamic acid (2 mM), glutamine (2 mM), glyceraldehyde 6-phosphate (2 mM), CaCl2 (5.0 mM), MgCl2 (5.0 mM), EDTA (10 mM), EGTA (10 mM), ATP (10 mM), GTP (10 mM), 5'-AMP (10 mM), adenosine (10 mM), hypoxanthine (10 mM)
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0072
8-azaadenine in double-stranded RNA
Homo sapiens
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pH 7.5, 30°C
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0.0012
adenine in double-stranded RNA
Homo sapiens
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pH 7.5, 30°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00004
8-azanebularine
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pH 7.5, 30°C
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
15
8-azanebularine
Homo sapiens
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pH 7.5, 30°C
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.002
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25°C, pH 7.9
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 8.5
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Tris or phosphate buffer
7.5
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assay at
7.8
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assay at
8
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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high expression
Manually annotated by BRENDA team
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spatiotemporal expression patterns for ADAR1 and ADAR2 in mouse forebrain. ADAR1 and ADAR2 are broadly distributed in most regions of the mouse forebrain, including the cerebral cortex, hippocampus, and diencephalon. High expression levels are maintained into adulthood. ADAR1 and ADAR2 are expressed in neurons but not astrocytes. ADAR1 mRNA has its lowest expression in the choroid plexus, cortex and hippocampus, while ADAR2 mRNA is least expressed in the cortex and hippocampus, with increased expression in the thalamus
Manually annotated by BRENDA team
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spatiotemporal expression patterns for ADAR1 and ADAR2 in mouse forebrain. ADAR1 and ADAR2 are broadly distributed in most regions of the mouse forebrain, including the cerebral cortex, hippocampus, and diencephalon. High expression levels are maintained into adulthood. ADAR1 and ADAR2 are expressed in neurons but not astrocytes. ADAR1 mRNA has its lowest expression in the choroid plexus, cortex and hippocampus, while ADAR2 mRNA is least expressed in the cortex and hippocampus, with increased expression in the thalamus
Manually annotated by BRENDA team
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ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis
Manually annotated by BRENDA team
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low expression in head kidney tissues
Manually annotated by BRENDA team
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embryonic
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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low expression
Manually annotated by BRENDA team
dADAR is expressed in the developing nervous system
Manually annotated by BRENDA team
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high expression
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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two major isoforms of ADAR1, P150 and P110, named following their molecular weights, are yielded by different RNA splicings. The 150 kDa isoform, translated from exon 1a, is the full length protein that is mainly distributed in the cytosol. The 110 kDa isoform, coded by other alternative first exons and lacking the Z-DNA binding domains, is mainly located in the cell nucleus
Manually annotated by BRENDA team
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ADAR2 localizes exclusively to the nucleus and accumulates in the nucleolus. In living cells, editing might be regulated by the intracellular compartmentalization of editing enzymes. ADAR2 shuttles between the nucleolus and the nucleoplasm; full-length and N-terminally truncated forms of ADAR1 are simultaneously expressed in HeLa cells. Because the N-terminus of ADAR1 contains a nuclear export signal, the full-length protein (150000 Da) localizes predominantly in the cytoplasm, whereas the N-terminally truncated forms (110000 Da) are exclusively nuclear and accumulate in the nucleolus. In living cells, editing might be regulated by the intracellular compartmentalization of editing enzymes. ADAR1 shuttles between the nucleolus, the nucleoplasm and the cytoplasm
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
12000
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x * 12000, the purified monomeric enzyme form is active, but it is not known if the enzyme functions strictly as a monomer, it may dimerize in the presence of substrate or associate in crude mixture with other cellular constituents, SDS-PAGE
90000
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2 * 90000, ADAR2 forms a stable enzymatically active homodimer complex, SDS-PAGE
98100
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gel filtration
110000
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x * 110000, isoform ADAR1S, SDS-PAGE
120000
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gel filtration
150000
180000
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gel filtration
300000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
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1 * 98100
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
the proteolytically defined Z-DNA binding domain Za of adenosine deaminase type 1 is crystallized in complex with the DNA oligomer d(TCGCGCG). The crystals are obtained from a solution containing ammonium sulfate as precipitating agent and belong to the tetragonal space group P4212
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in HEK-293T cells
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expressed in Pichia pastoris
expression in Pichia pastoris
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expression in Saccharomyces cerevisiae
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expression in Sf9 cells
expression in Sf9 cells; expression in Sf9 cells
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full-length human ADAR2 is overexpressed in Saccharomyces cerevisiae
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large-scale overexpression in Saccharomyces cerevisiae with an N-terminal histidine tag that is cleaved by the tobacco etch virus protease
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overexpression in Escherichia coli and Pichia pastoris, advantages of using Pichia pastoris for overexpression, large scale expression
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the Z-DNA binding domain is expressed as a C-terminal glutathione S-transferase fusion in Escherichia coli using a pGEX-5X1 cloning vector
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
ADAR1 and ADAR2 are expressed at low levels in the fetal brain, and increase gradually over time. High expression levels were maintained into adulthood
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ADAR1 is interferon-inducible, ADAR2 is constitutively expressed
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CiADAR1 mRNA expression is rapidly and significantly elevated after dsRNA (poly(I:C)) stimulation; mRNA expression of CiADAR1 is significantly upregulated and reaches peak at 24 h post grass carp reovirus challenge in vivo and in vitro
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isoform ADAR1L is induced by interferon gamma or HIV-1 infection in primary macrophages but not in primary CD4 T cells
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isoform P110 is constitutively expressed in cells. In early mouse embryos, isoform P110 is expressed on day 10.5, but P150 was not expressed until day 15
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the dADAR expression pattern is determined by in situ hybridization to whole Drosophila embryos of various developmental stages. A low level of nonspecific staining is seen in early stage 13 embryos (end of germ-band retraction), specific staining is seen by late stage 13 after condensation of the ventral nerve cord occurs. Staining then proceedes to intensify within the central nervous system, reaching high levels in the embryonic ventral nerve cord and brain by stage 16
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information