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Information on EC 3.5.4.38 - single-stranded DNA cytosine deaminase and Organism(s) Homo sapiens and UniProt Accession Q9NRW3

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EC Tree
IUBMB Comments
The enzyme exclusively catalyses deamination of cytosine in single-stranded DNA. It preferentially deaminates five-nucleotide bubbles. The optimal target consists of a single-stranded NWRCN motif (W = A or T, R = A or G) . The enzyme initiates antibody diversification processes by deaminating immunoglobulin sequences.
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Homo sapiens
UNIPROT: Q9NRW3
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
cytosine in single-stranded DNA
+
=
uracil in single-stranded DNA
+
Synonyms
apobec3b, apobec3a, apobec3f, activation-induced deaminase, apobec3h, apobec3c, apobec3d, single-stranded dna cytosine deaminase, apobec3z1, ssdna cytidine deaminase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
activation-induced cytidine deaminase
activation-induced deaminase
-
single-stranded (ss)DNA deoxycytidine deaminase
-
ssDNA cytidine deaminase
-
SYSTEMATIC NAME
IUBMB Comments
single-stranded DNA cytosine aminohydrolase
The enzyme exclusively catalyses deamination of cytosine in single-stranded DNA. It preferentially deaminates five-nucleotide bubbles. The optimal target consists of a single-stranded NWRCN motif (W = A or T, R = A or G) [2]. The enzyme initiates antibody diversification processes by deaminating immunoglobulin sequences.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
cytosine in single-stranded DNA + H2O
uracil in single-stranded DNA + NH3
show the reaction diagram
5-methylcytosine in single-stranded DNA + H2O
?
show the reaction diagram
the enzyme exhibits low activity toward 5-methylcytosine n single-stranded DNA
-
-
?
cytosine in single-stranded DNA + H2O
uracil in single-stranded DNA + NH3
show the reaction diagram
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
cytosine in single-stranded DNA + H2O
uracil in single-stranded DNA + NH3
show the reaction diagram
the APOBEC3 enzymes are a double-edged sword that can catalyze deamination of cytosine in genomic DNA, which results in potential genomic instability due to the many mutagenic fates of uracil. The enzymes must be able to efficiently deaminate transiently available single-stranded DNA during reverse transcription, replication, or transcription. Specific biochemical characteristics promote deamination in each situation to increase enzyme efficiency through processivity, rapid enzyme cycling between substrates, or oligomerization state in DNA
-
-
?
cytosine in single-stranded DNA + H2O
uracil in single-stranded DNA + NH3
show the reaction diagram
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zinc
coordination of a secondary zinc ion enhances deamination activity up to 160%ing is pinpointed to loop-3 which harbors a catalytically essential and spatially conserved asparagine at its N-terminus
additional information
the enzyme requires a tightly bound metal ion for its action
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
-
additional information
no inbibition by EDTA
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
RNA
RNA binding is integral to APOBEC3H function. RNA-mediated dimerization alters the interactions of the enzyme with ssDNA and other RNA molecules
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
Km of glutathione S-transferase-AID for the hot-spot transcription bubble substrate HS1bub7 is between 10 and 15 nM. It is not possible to estimate the Km for the cold-spot bubble (i.e., CS1bub7) since the substrate saturation kinetics is not observed. However, as the velocity continues to increase beyond the highest substrate concentration tested, the Km is likely to be severalfold higher for CS1bub7 than for HS1bub7
-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.6 - 9
wide range of pH
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22 - 37
the enzyme works with varying efficiencies from room temperature to 37°C
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
APOBEC3G is preferentially expressed in mesenchymal gliomas
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
the APOBEC3 family has many roles, such as restricting endogenous and exogenous retrovirus replication and retrotransposon insertion events and reducing DNA-induced inflammation
malfunction
metabolism
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ABC3C_HUMAN
190
0
22826
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
184000
tetrameric enzyme form, APOBEC3B predominantly forms tetramers and a small proportion existed as dimers, gel filtration
92000
dimeric enzyme form, APOBEC3B predominantly forms tetramers and a small proportion existed as dimers, gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
monomer
non-phosphorylated activation-induced deaminase, is catalytically active as a monomer on single stranded DNA in vitro, including single-stranded DNA found in loops similar to those transiently formed in the immunoglobulin switch regions during transcription
tetramer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
ubiquitination
the enzyme is polyubiquitinated in the nucleus. Ubiquitin-mediated nuclear degradation of the enzyme is part of a multilayer control that contributes to the regulation of enzyme function during hypermutation and class switch recombination
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
generation of a panel of free or DNA-bound AID models based on eight recently resolved APOBEC isoform structures. The majority of AID:DNA complexes would be inactive due to substrate binding such that a cytidine is not positioned for deamination. Most AID conformations exhibit fully or partially occluded catalytic pockets
generation of a panel of free or DNA-bound AID models based on eight resolved APOBEC structures. The majority of AID:DNA complexes would be inactive due to substrate binding such that a cytidine is not positioned for deamination. Most AID conformations exhibit fully or partially occluded catalytic pockets
hanging drop vapor diffusion method
hanging drop vapor diffusion method, APOBEC3B catalytic domain crystal structures including a dCMP-bound form
modeling of structure. Residue Arg211 in loop 1 is the gatekeeper coordinating DNA. ssDNA binds to the C-terminal domain in a U-shape, and loop 1 undergoes major conformational changes to open up the active site for DNA binding. Residue D314 defines substrate specificity for thymidine over cytidine at -1 position. An auto-inhibited conformation in the C-terminal domain restricts access and binding of DNA to the active site
sitting drop vapor diffusion method at 4°C, crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA at 1.86 A resolution
sitting drop vapor-diffusion method, crystal structure of the C-terminal catalytic domain of the enzyme (APOBEC3F) in complex with a 10 nucleotide ssDNA composed of a poly-thymine sequence
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C101S
mutant lacks bth DNA and RNA deaminase activity
C90A
catalytically inactive
E58Q/C87A/C90A
the mutant enzyme does not bind to single-stranded DNA at all, though it retains some binding to RNA
E72D
mutant is moderately impaired in a ssDNA deamination assay but capable of RNA deamination
G56N
mutation at the N-terminus end of loop-3 does not bestow deamination activity
H248S/H250S
increase in the concentration of zinc does not increase deamination activity
K352A/K355A/K358A
the product formation of the mutant enzyme can not reach saturation even when the maximum protein concentration is obtained
N244A
abolishes activity
N244D
abolishes activity
N244G
abolishes activity
N244L
abolishes activity
N244Q
about 3% residual activity
P134A
about 89% of wild-type RNA deamination activity
P210A
almost abolishes activity
P210G
almost abolishes activity
Y333A
the product formation of the mutant enzyme can not reach saturation even when the maximum protein concentration is obtained
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
65
30 min, protein is active
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme displays a different stability depending on the specific cell compartment in which it is located. In a Burkitt’s lymphoma cell line the half-life of activation-induced cytidine deaminase is markedly reduced in the nucleus. This destabilization is accompanied by a polyubiquitination that is revealed in the presence of proteasome inhibitors. The same compartment-specific degradation is observed in activated mouse B cells, and also in a non–B cell line
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
construction of stable transformants (mouse hybridoma cells) expressing human activation-induced cytidine deaminase
expression HEK 293T cells
expression in Escherichia coli
expression in Escherichia coli as a glutathione S-transferase fusion protein
expression in Escherichia coli strain C43(DE3)pLysS
expression in Escherichia coli. Human activation-induced cytidine deaminase purified from Escherichia coli is active without prior treatment with a ribonuclease and deaminates cytosines in plasmid DNA in vitro
expression in Sf9 cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression is increased by epidermal growth factor, tumor necrosis factor alpha, or sodium butyrate
the enzyme is expressed in response to antigen activation
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
APOBEC3G mediated checkpoint activation through checkpoint kinase 2 (Chk2) is one of the critical regulatory mechanisms that underlies the preferential DNA damage checkpoint response and radioresistance of Glioma Initiating Cells. Thus, anti-APOBEC3G therapy may synergize with radiotherapy and other current treatments to overcome the therapeutic resistance of gliomas. APOBEC3G represents a potential molecular target for novel therapeutics that will improve the treatment outcome of glioma patients
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Larijani, M.;Petrov, A.P.; Kolenchenko, O.; Berru, M.; Krylov, S.N.; Martin, A.
AID associates with single-stranded DNA with high affinity and a long complex half-life in a sequence-independent manner
Mol. Cell. Biol.
27
20-30
2007
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Vallur, A.C.; Yabuki, M.; Larson, E.D.; Maizels, N.
AID in antibody perfection
Cell. Mol. Life Sci.
64
555-565
2007
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Brar, S.S.; Sacho, E.J.; Tessmer, I.; Croteau, D.L.; Erie, D.A.; Diaz, M.
Activation-induced deaminase, AID, is catalytically active as a monomer on single-stranded DNA
DNA Repair
7
77-87
2007
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Carpenter, M.A.; Rajagurubandara, E.; Wijesinghe, P.; Bhagwat, A.S.
Determinants of sequence-specificity within human AID and APOBEC3G
DNA Repair
9
579-587
2010
Homo sapiens (Q9GZX7), Homo sapiens
Manually annotated by BRENDA team
Lee, S.A.; Parsa, J.Y.; Martin, A.; Baker, M.D.
Activation-induced cytidine deaminase induces DNA break repair events more frequently in the Ig switch region than other sites in the mammalian genome
Eur. J. Immunol.
37
3529-3539
2007
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Wang, J.H.
The role of activation-induced deaminase in antibody diversification and genomic instability
Immunol. Res.
55
287-297
2013
Homo sapiens (Q9GZX7), Mus musculus (Q9WVE0)
Manually annotated by BRENDA team
Dickerson, S.K.; Market, E.; Besmer, E.; Papavasiliou, F.N.
AID mediates hypermutation by deaminating single stranded DNA
J. Exp. Med.
197
1291-1296
2003
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Aoufouchi, S.; Faili, A.; Zober, C.; D'Orlando, O.; Weller, S.; Weill, J.C.; Reynaud, C.A.
Proteasomal degradation restricts the nuclear lifespan of AID
J. Exp. Med.
205
1357-1368
2008
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Miyazaki, Y.; Inoue, H.; Kikuchi, K.; Ochiai, K.; Kusama, K.
Activation-induced cytidine deaminase mRNA expression in oral squamous cell carcinoma-derived cell lines is upregulated by inflammatory cytokines
J. Oral Sci.
54
71-75
2012
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Larijani, M.; Martin, A.
Single-stranded DNA structure and positional context of the target cytidine determine the enzymatic efficiency of AID
Mol. Cell. Biol.
27
8038-8048
2007
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Sohail, A.; Klapacz, J.; Samaranayake, M.; Ullah, A.; Bhagwat, A.S.
Human activation-induced cytidine deaminase causes transcription-dependent, strand-biased C to U deaminations
Nucleic Acids Res.
31
2990-2994
2003
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Bransteitter, R.; Pham, P.; Scharff, M.D.; Goodman, M.F.
Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase
Proc. Natl. Acad. Sci. USA
100
4102-4107
2003
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Pasqualucci, L.; Kitaura, Y.; Gu, H.; Dalla-Favera, R.
PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells
Proc. Natl. Acad. Sci. USA
103
395-400
2005
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Meyers, G.; Ng, Y.S.; Bannock, J.M.; Lavoie, A.; Walter, J.E.; Notarangelo, L.D.; Kilic, S.S.; Aksu, G.; Debre, M.; Rieux-Laucat, F.; Conley, M.E.; Cunningham-Rundles, C.; Durandy, A.; Meffre, E.
Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans
Proc. Natl. Acad. Sci. USA
108
11554-11559
2011
Homo sapiens
Manually annotated by BRENDA team
Hou, S.; Silvas, T.V.; Leidner, F.; Nalivaika, E.A.; Matsuo, H.; Kurt Yilmaz, N.; Schiffer, C.A.
Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B
J. Chem. Theory Comput.
15
637-647
2019
Homo sapiens (Q9UH17), Homo sapiens
Manually annotated by BRENDA team
Sharma, S.; Patnaik, S.K.; Taggart, R.T.; Kannisto, E.D.; Enriquez, S.M.; Gollnick, P.; Baysal, B.E.
APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages
Nat. Commun.
6
6881
2015
Homo sapiens (P31941)
Manually annotated by BRENDA team
Hu, W.; Begum, N.A.; Mondal, S.; Stanlie, A.; Honjo, T.
Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase
Proc. Natl. Acad. Sci. USA
112
5791-5796
2015
Homo sapiens (Q9GZX7)
Manually annotated by BRENDA team
Marx, A.; Galilee, M.; Alian, A.
Zinc enhancement of cytidine deaminase activity highlights a potential allosteric role of loop-3 in regulating APOBEC3 enzymes
Sci. Rep.
5
18191
2015
Homo sapiens (P31941), Homo sapiens (Q9HC16)
Manually annotated by BRENDA team
Sharma, S.; Patnaik, S.K.; Taggart, R.T.; Baysal, B.E.
The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme
Sci. Rep.
6
39100
2016
Homo sapiens (Q9HC16)
Manually annotated by BRENDA team
King, J.J.; Manuel, C.A.; Barrett, C.V.; Raber, S.; Lucas, H.; Sutter, P.; Larijani, M.
Catalytic pocket inaccessibility of activation-induced cytidine deaminase is a safeguard against excessive mutagenic activity
Structure
23
615-627
2015
Homo sapiens, Homo sapiens (P31941)
Manually annotated by BRENDA team
Adolph, M.B.; Love, R.P.; Chelico, L.
Biochemical basis of APOBEC3 deoxycytidine deaminase activity on diverse DNA substrates
ACS Infect. Dis.
4
224-238
2018
Homo sapiens (P31941), Homo sapiens (Q6NTF7), Homo sapiens (Q8IUX4), Homo sapiens (Q96AK3), Homo sapiens (Q9HC16), Homo sapiens (Q9NRW3), Homo sapiens (Q9UH17)
Manually annotated by BRENDA team
Shi, K.; Carpenter, M.A.; Kurahashi, K.; Harris, R.S.; Aihara, H.
Crystal structure of the DNA deaminase APOBEC3B catalytic domain
J. Biol. Chem.
290
28120-28130
2015
Homo sapiens (Q9UH17)
Manually annotated by BRENDA team
Ito, F.; Fu, Y.; Kao, S.A.; Yang, H.; Chen, X.S.
Family-wide comparative analysis of cytidine and methylcytidine deamination by eleven human APOBEC proteins
J. Mol. Biol.
429
1787-1799
2017
Homo sapiens (P31941), Homo sapiens (Q6NTF7), Homo sapiens (Q8IUX4), Homo sapiens (Q96AK3), Homo sapiens (Q9HC16), Homo sapiens (Q9NRW3), Homo sapiens (Q9UH17), Homo sapiens
Manually annotated by BRENDA team
Feng, Y.; Wong, L.; Morse, M.; Rouzina, I.; Williams, M.C.; Chelico, L.
RNA-mediated dimerization of the human deoxycytidine deaminase APOBEC3H influences enzyme activity and interaction with nucleic acids
J. Mol. Biol.
430
4891-4907
2018
Homo sapiens (Q6NTF7), Homo sapiens
Manually annotated by BRENDA team
Fang, Y.; Xiao, X.; Li, S.X.; Wolfe, A.; Chen, X.S.
Molecular interactions of a DNA modifying enzyme APOBEC3F catalytic domain with a single-stranded DNA
J. Mol. Biol.
430
87-101
2018
Homo sapiens (Q8IUX4)
Manually annotated by BRENDA team
Maiti, A.; Myint, W.; Kanai, T.; Delviks-Frankenberry, K.; Sierra Rodriguez, C.; Pathak, V.K.; Schiffer, C.A.; Matsuo, H.
Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with sDNA
Nat. Commun.
9
2460
2018
Homo sapiens (Q9HC16)
Manually annotated by BRENDA team
Adolph, M.B.; Love, R.P.; Feng, Y.; Chelico, L.
Enzyme cycling contributes to efficient induction of genome mutagenesis by the cytidine deaminase APOBEC3B
Nucleic Acids Res.
45
11925-11940
2017
Homo sapiens (Q9UH17)
Manually annotated by BRENDA team
Wang, Y.; Wu, S.; Zheng, S.; Wang, S.; Wali, A.; Ezhilarasan, R.; Sulman, E.P.; Koul, D.; Alfred Yung, W.K.
APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death
Oncotarget
8
54285-54296
2017
Homo sapiens (Q9HC16)
Manually annotated by BRENDA team
Kamba, K.; Nagata, T.; Katahira, M.
Catalytic analysis of APOBEC3G involving real-time NMR spectroscopy reveals nucleic acid determinants for deamination
PLoS ONE
10
e0124142
2015
Homo sapiens (Q9HC16)
Manually annotated by BRENDA team
Shi, K.; Demir, O.e.; Carpenter, M.A.; Wagner, J.; Kurahashi, K.; Harris, R.S.; Amaro, R.E.; Aihara, H.
Conformational switch regulates the DNA cytosine deaminase activity of human APOBEC3B
Sci. Rep.
7
17415
2017
Homo sapiens (Q9UH17), Homo sapiens
Manually annotated by BRENDA team