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Information on EC 3.6.1.53 - Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase
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EC Tree
3.6.1.53 Mn2+-dependent ADP-ribose/CDP-alcohol diphosphataseIUBMB Comments
Requires Mn2+. Unlike EC 3.6.1.13, ADP-ribose diphosphatase, it cannot utilize Mg2+. ADP-D-ribose, CDP-choline, CDP-ethanolamine and ADP are substrates for this enzyme but ADP-D-glucose, UDP-D-glucose, CDP-D-glucose, CDP, CMP and AMP are not hydrolysed . In rat, the enzyme is found predominantly in thymus and spleen.
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Word Map
- 3.6.1.53
-
nonenzymatic
-
adp-ribosylation
-
cadpr
- catalases
- dithiothreitol
-
cdp-alcohols
- n-acetyl-p-benzoquinoneimine
-
entrance
- chloramphenicol
-
chlorination
-
phosphohydrolysis
- acetaminophen
-
metallo-dependent
- nitroprusside
-
phosphoanhydride
- peroxidases
-
napqi
-
venezuelae
-
pyrophosphatases
-
brominating
-
hepatotoxicity
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
adpribase-mn, adpribase-i, adpribase-ii, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ADPRibase-Mn
Mn2+-dependent ADP-ribose/CDP-alcohol pyrophosphatase
ADPRibase-Mn
-
-
-
-
Mn2+-dependent ADP-ribose/CDP-alcohol pyrophosphatase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ADP-D-ribose + H2O = AMP + D-ribose 5-phosphate
-
-
-
-
CDP-choline + H2O = CMP + phosphocholine
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
CDP-choline phosphohydrolase
Requires Mn2+. Unlike EC 3.6.1.13, ADP-ribose diphosphatase, it cannot utilize Mg2+. ADP-D-ribose, CDP-choline, CDP-ethanolamine and ADP are substrates for this enzyme but ADP-D-glucose, UDP-D-glucose, CDP-D-glucose, CDP, CMP and AMP are not hydrolysed [2]. In rat, the enzyme is found predominantly in thymus and spleen.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
adenosine 5'-diphospho-5'-adenosine + H2O
AMP
-
-
45% of the activity with ADP-ribose
-
?
ADP + H2O
?
27% activity at 0.5 mM substrate compared to ADP-ribose
-
-
?
CDP-ethanolamine + H2O
?
89% activity at 0.5 mM substrate compared to ADP-ribose
-
-
?
CDP-glycerol + H2O
?
89% activity at 0.5 mM substrate compared to ADP-ribose
-
-
?
IDP-ribose + H2O
IMP + D-ribose 5-phosphate
-
-
105% of the activity with ADP-ribose
-
?
ADP-ribose + H2O
AMP + D-ribose 5-phosphate
100% activity at 0.5 mM substrate
-
-
?
CDP-choline + H2O
CMP + phosphocholine
-
140% of the activity with ADP-ribose
-
-
?
CDP-choline + H2O
CMP + phosphocholine
156% of the activity with ADP-ribose
-
-
?
CDP-choline + H2O
CMP + phosphocholine
140% activity at 0.5 mM substrate compared to ADP-ribose
-
-
?
CDP-ethanolamine + H2O
CMP + phosphoethanolamine
84% of the activity with ADP-ribose
-
-
?
CDP-ethanolamine + H2O
CMP + phosphoethanolamine
-
89% of the activity with ADP-ribose
-
-
?
CDP-glycerol + H2O
CMP + phosphoglycerol
103% of the activity with ADP-ribose
-
-
?
CDP-glycerol + H2O
CMP + phosphoglycerol
-
89% of the activity with ADP-ribose
-
-
?
cyclic ADP-ribose + H2O
N1-(5-phosphoribosyl)-AMP
-
cADPR is an ADPRibase-Mn ligand and substrate
-
-
?
cyclic ADP-ribose + H2O
N1-(5-phosphoribosyl)-AMP
-
ADPRibase-Mn activity on cyclic ADP-ribose is 65fold less efficient than on ADP-ribose
-
-
?
cyclic ADP-ribose + H2O
N1-(5-phosphoribosyl)-AMP
-
product determination and analysis, cADPR is an ADPRibase-Mn ligand and substrate. ADPRibase-Mn activity on cADPR is 65fold less efficient than on ADP-ribose, the best substrate. Phosphohydrolytic pattern of the reaction, overview
-
-
?
additional information
?
-
-
very poor substrate: cyclic ADP-ribose. No substrate: ADP-glucose, UDP-glucose, CDP-glucose, CDP, CMP, AMP or 3',5'-cAMP
-
-
-
additional information
?
-
very poor substrate: cyclic ADP-ribose. No substrate: ADP-glucose, UDP-glucose, CDP-glucose, CDP, CMP, AMP or 3',5'-cAMP
-
-
-
additional information
?
-
-
ADPRibase-Mn hydrolyzes the phosphoanhydride linkages of ADP-ribose, CDP-choline, CDP-glycerol, CDP-ethanolamine, and ADP with decreasing efficiencies, requiring low micromolar Mn2+ concentrations not substituted by Mg2+. ADPRibase-Mn hydrolyzes ADP-ribose, CDP-choline, CDP-glycerol and CDP-ethanolamine with decreasing catalytic efficiencies
-
-
-
additional information
?
-
ADP-glucose, UDP-glucose, CDP-glucose, CDP, CMP, and AMP are not hydrolysed
-
-
-
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cyclic ADP-ribose + H2O
N1-(5-phosphoribosyl)-AMP
-
cADPR is an ADPRibase-Mn ligand and substrate
-
-
?
additional information
?
-
-
ADPRibase-Mn hydrolyzes the phosphoanhydride linkages of ADP-ribose, CDP-choline, CDP-glycerol, CDP-ethanolamine, and ADP with decreasing efficiencies, requiring low micromolar Mn2+ concentrations not substituted by Mg2+. ADPRibase-Mn hydrolyzes ADP-ribose, CDP-choline, CDP-glycerol and CDP-ethanolamine with decreasing catalytic efficiencies
-
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mn2+
additional information
Mn2+
required, similar activatory effects with all the substrates tested. Km values around 1 microM and 2.5 mM Mn2+ for ADP-ribose hydrolysis
Mn2+
dependent on, ADPRibase-Mn is inactive without added Mn2+, and it shows a high affinity for the cation, since saturation is observed at low-micromolar concentrations of Mn2+ well below the substrate concentration (0.5 mM), in no case can Mg2+ replace Mn2+; required. Concentration of MnCl2 giving the half-maximal rate is 0.001-0.004 mM. Mn2+ cannot be replaced by Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
incubation with 2.5 mM EDTA does not affect ADPRibase-Mn activity; not inhibitory: EDTA up to 2.5 mM
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.76
2',3'-cAMP
wild-type, pH 7.5, temperature not specified in the publication
1.7
2',3'-cAMP
mutant H97A, pH 7.5, temperature not specified in the publication
0.201
ADP
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
0.039
ADP-ribose
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
0.053
ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
0.071
ADP-ribose
mutant H97A, pH 7.5, temperature not specified in the publication
1.15
ADP-ribose
mutant F37A/L196A, pH 7.5, 37°C; mutant F37A, pH 7.5, 37°C
0.3
CDP-choline
pH 7.5, 37°C; recombinant, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
12
CDP-choline
wild-type, pH 7.5, temperature not specified in the publication
43
CDP-choline
mutant H97A, pH 7.5, temperature not specified in the publication
1.422
CDP-ethanolamine
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
3.9
CDP-ethanolamine
wild-type, pH 7.5, temperature not specified in the publication
31
CDP-ethanolamine
mutant H97A, pH 7.5, temperature not specified in the publication
0.304
CDP-glycerol
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
2
CDP-glycerol
wild-type, pH 7.5, temperature not specified in the publication
6.3
CDP-glycerol
mutant H97A, pH 7.5, temperature not specified in the publication
0.19
cyclic ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
16.9
2',3'-cAMP
wild-type, pH 7.5, temperature not specified in the publication
29.7
2',3'-cAMP
mutant H97A, pH 7.5, temperature not specified in the publication
4.4
ADP
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
0.4
ADP-ribose
mutant H97A, pH 7.5, temperature not specified in the publication
12.8
ADP-ribose
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 01 mM MnCl2, at 37°C
18
ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
0.8
CDP-choline
mutant H97A, pH 7.5, temperature not specified in the publication
28.5
CDP-choline
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
67.2
CDP-choline
wild-type, pH 7.5, temperature not specified in the publication
2.1
CDP-ethanolamine
mutant H97A, pH 7.5, temperature not specified in the publication
41.3
CDP-ethanolamine
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
125.2
CDP-ethanolamine
wild-type, pH 7.5, temperature not specified in the publication
0.8
CDP-glycerol
mutant H97A, pH 7.5, temperature not specified in the publication
28.1
CDP-glycerol
pH 7.5, 37°C; recombinant enzyme, in 50 mM Tris-HCl (pH 7.5), 0.1 mM MnCl2, at 37°C
95.6
CDP-glycerol
wild-type, pH 7.5, temperature not specified in the publication
0.005
cyclic ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4
2',3'-cAMP
mutant F37A/L196A, pH 7.5, 37°C; mutant F37A/L196F/C253A, pH 7.5, 37°C
18
2',3'-cAMP
mutant H97A, pH 7.5, temperature not specified in the publication
22
2',3'-cAMP
wild-type, pH 7.5, temperature not specified in the publication
0.011
ADP
mutant H97A, pH 7.5, temperature not specified in the publication
5.9
ADP-ribose
mutant H97A, pH 7.5, temperature not specified in the publication
340
ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
0.02
CDP-choline
mutant H97A, pH 7.5, temperature not specified in the publication
5.6
CDP-choline
wild-type, pH 7.5, temperature not specified in the publication
0.07
CDP-ethanolamine
mutant H97A, pH 7.5, temperature not specified in the publication
32
CDP-ethanolamine
wild-type, pH 7.5, temperature not specified in the publication
0.12
CDP-glycerol
mutant H97A, pH 7.5, temperature not specified in the publication
48
CDP-glycerol
wild-type, pH 7.5, temperature not specified in the publication
0.028
cyclic ADP-ribose
wild-type, pH 7.5, temperature not specified in the publication
0.9
cyclic ADP-ribose
mutant F37A/L196A, pH 7.5, 37°C; mutant L196A, pH 7.5, 37°C
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
; bifunctional Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase
UniProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
ADPRibase-Mn activity in spleen is 2.5-5fold higher than in liver and muscle
brenda
ADPRibase-Mn activity in thymus is 2.5-5fold higher than in liver and muscle
brenda
additional information
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40000
1 * 39360, calculated, 1 * 40000, SDS-PAGE, enzyme plus N-terminal extension GPLGSPNS left after proteolysis of recombinant fusion protein
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
1 * 30000, gel filtration; 1 * 39360, calculated, 1 * 40000, SDS-PAGE, enzyme plus N-terminal extension GPLGSPNS left after proteolysis of recombinant fusion protein
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CRYSTALLIZATION/commentary
ORGANISM
UNIPROT
LITERATURE
substrate-docking studies point to a role of His-97 in catalysis by orientation, and to a bidentate water bridging the dinuclear metal center as the potential nucleophile
substrate docking on a homology model of human ADPRibase-Mn suggests possible interactions of ADP-ribose with residue Cys253, within the metallo-dependent phosphatases signature with Gln27, Asn110, His111, or in unique structural regions of the ADPRibase-Mn family, residues Phe37 and Arg43 and Phe210
coordinates of rat ADPRibase-Mn, modelled by homology to the X-ray structure of its zebrafish orthologue, taken from the SWISS-MODEL repository, accession code q5m88. cADPR docking to a model of ADPRibase-Mn and molecular dynamics simulation, ADPRibase-Mn complexes with docked ligands show the active center in a closed conformation, overview
-
homology modeling based on crystal structure of the Danio rerio protein, Protein Data Base entry 2NXF, and docking of ADP-ribose
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C253A
10fold increase of the catalytic efficiency for cyclic ADP-ribose; Cys253 is hindering for cADPR phosphohydrolase activity, specific tenfold gain of efficiency with cyclic ADP-ribose
F210A
mutation lowers 40-70fold the catalytic efficiency for ADP-ribose, CDP-choline and 2',3'-cAMP hydrolysis, and 500fold for cyclic ADP-ribose
F37A/L196A
modest enhancement of the inhibitory effect over that of the F37A point mutation
F37A/L196F
modest enhancement of the inhibitory effect over that of the F37A point mutation
F37A/L196F/C253A
cyclic ADP-ribose is the best substrate, with a 8fold increase in catalytic efficiency compared to wild-type
H111A
marked decrease in efficiency with all substrates except 2',3'-cAMP
H111N
marked decrease in efficiency with all substrates except 2',3'-cAMP
L196A
modest 2-5fold decrease of catalytic efficiency with the substrates tested
N110A
reduction of catalytic efficiency is stronger for the hydrolysis of CDP-choline or 2',3'-cAMP than for the hydrolysis of ADP-ribose or cADPR. The decrease of kcat value is stronger for the hydrolysis of 2',3'-cAMP
Q27H
for ADP-ribose, modest negative effects of similar magnitude in catalysis and in substrate binding. For CDP-choline, the substitution affects only binding. For 2',3'-cAMP, the substitution affects catalysis, not binding
R43A
Arg43 is essential for catalysis, drastic efficiency loss of the mutant
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 8
the activities towards ADP and CDP-alcohols are highest at pH 6-8 and decrease abruptly at higher pH
690823
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION/commentary
ORGANISM
UNIPROT
LITERATURE
glutathione-Sepharose column chromatography; recombinant GSt-fusion protein, in-column proteolysis of fusion
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CLONED/commentary
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 cells; expression as GST-fusion protein
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Canales, J.; Pinto, R.M.; Costas, M.J.; Hernandez, M.T.; Miro, A.; Bernet, D.; Fernandez, A.; Cameselle, J.C.
Rat liver nucleoside diphosphosugar or diphosphoalcohol pyrophosphatase different from nucleotide pyrophosphatase or phosphodiesterase I: substrate specificities of Mg2+- and/or Mn2+-depeneent hydrolases acting on ADP-ribose
Biochim. Biophys. Acta
1246
167-177
1995
Rattus norvegicus
brenda
Canales, J.; Fernandez, A.; Ribeiro, J.M.; Cabezas, A.; Rodrigues, J.R.; Cameselle, J.C.; Costas, M.J.
Mn2+-dependent ADP-ribose/CDP-alcohol pyrophosphatase: a novel metallophosphoesterase family preferentially expressed in rodent immune cells
Biochem. J.
413
103-113
2008
Mus musculus, Mus musculus (Q99KS6), Rattus norvegicus (Q5M886)
brenda
Canales, J.; Fernandez, A.; Rodrigues, J.R.; Ferreira, R.; Ribeiro, J.M.; Cabezas, A.; Costas, M.J.; Cameselle, J.C.
Hydrolysis of the phosphoanhydride linkage of cyclic ADP-ribose by the Mn(2+)-dependent ADP-ribose/CDP-alcohol pyrophosphatase
FEBS Lett.
583
1593-1598
2009
Rattus norvegicus
brenda
Cabezas, A.; Ribeiro, J.; Rodrigues, J.; Lopez-Villamizar, I.; Fernandez, A.; Canales, J.; Pinto, R.; Costas, M.; Cameselle, J.
Molecular bases of catalysis and ADP-ribose preference of human Mn2+-dependent adpribose/CDP-alcohol diphosphatase and conversion by mutagenesis to a preferential cyclic ADP-ribose phosphohydrolase
PLoS ONE
10
e0118680
2015
Homo sapiens, Homo sapiens (W0NWJ0)
brenda
Rodrigues, J.; Fernandez, A.; Canales, J.; Cabezas, A.; Ribeiro, J.; Costas, M.; Cameselle, J.
Characterization of Danio rerio Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase, the structural prototype of the ADPRibase-Mn-like protein family
PLoS ONE
7
e42249
2012
Danio rerio, Danio rerio (Q7T291)
brenda
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