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Information on EC 3.6.1.53 - Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase and Organism(s) Homo sapiens
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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 . The mammalian enzyme hydrolyses cyclic ADP-ribose to 1-(5-phospho-beta-D-ribosyl)-AMP with ~100-fold lower efficiency than ADP-D-ribose . In rat, the enzyme is found predominantly in thymus and spleen.
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Word Map
- 3.6.1.53
- dithiothreitol
-
adp-ribosylation
-
nonenzymatic
-
phosphohydrolysis
-
cadpr
-
napqi
- pyrophosphatases
-
cdp-alcohols
- n-acetyl-p-benzoquinoneimine
- nitroprusside
-
hepatotoxicity
- acetaminophen
- rodent
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
adpribase-i, adpribase-ii, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ADPRibase-Mn
Mn2+-dependent ADP-ribose/CDP-alcohol pyrophosphatase
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ADPRibase-Mn
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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]. The mammalian enzyme hydrolyses cyclic ADP-ribose to 1-(5-phospho-beta-D-ribosyl)-AMP with ~100-fold lower efficiency than ADP-D-ribose [3]. In rat, the enzyme is found predominantly in thymus and spleen.
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
additional information
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ADP-ribose/CDP-alcohol diphosphatase (ADPRibase-Mn) acts as cyclic ADP-ribose (cADPR) phosphohydrolase with much lower efficiency than on its major substrates
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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
additional information
?
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ADP-ribose/CDP-alcohol diphosphatase (ADPRibase-Mn) acts as cyclic ADP-ribose (cADPR) phosphohydrolase with much lower efficiency than on its major substrates
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
ADPRibase-Mn enzymes contain the dinuclear metal centre typical of the metallo-dependent phosphatases SCOP2 superfamily, forming within it a family of their own named as ADPRibase-Mn-like. ADPRibase-Mn proteins constitute also a functional family in the CATH classification, within cluster SC:3 of superfamily 3.60.21.10
physiological function
cyclic ADP-ribose (cADPR) is a messenger for Ca2+ mobilization. Its turnover is believed to occur by glycohydrolysis to ADP-ribose. ADP-ribose/CDP-alcohol diphosphatase (ADPRibase-Mn) acts as cADPR phosphohydrolase with much lower efficiency than on its major substrates
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ADPRM_HUMAN
342
0
39529
Swiss-Prot
other Location (Reliability: 1)
W0NWJ0_HUMAN
342
0
39529
TrEMBL
other Location (Reliability: 1)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C253A
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
F37A/L196F/C253G
site-directed mutagenesis, the mutant with a smaller residue 253 shows increased cADPR specificity
F37A/L196F/D250A/C253G
site-directed mutagenesis, the quadruple mutant shows a detrimental effect of the D250A substitution on the efficiency with all substrates (1.3-3.4fold decrease), and more markedly so for cADPR, such that the substrate efficiency ratios are less favourable than for the triple mutant F37A/ L196F/C253G
F37A/L196F/V252A/C253G
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
additional information
design of mutations at or near residue 253 of human ADPRibase-Mn, in the vicinity of the adenine N1-linked (northern) ribose of cADPR, for altering the substrate specificity of the enzyme, overview
C253A
Cys253 is hindering for cADPR phosphohydrolase activity, specific tenfold gain of efficiency with cyclic ADP-ribose
F37A/L196F/C253A
cyclic ADP-ribose is the best substrate, with a 8fold increase in catalytic efficiency compared to wild-type
F37A/L196F/C253A
site-directed mutagenesis, specific cyclic ADP-ribose phosphohydrolase obtained by mutagenic engineering of Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase. Mutagenesis of human ADPRibase-Mn at Phe37, Leu196 and Cys253 alters its specificity, the best substrate of the mutant is cyclic ADP-ribose (cADPR), the Cys253 mutation is essential for cADPR preference. The proximity to the northern ribose of cADPR in docking models indicates Cys253 is a steric constraint for cADPR positioning
F37A/L196F/V252A/C253G
site-directed mutagenesis, the mutant with displays the desired specificity, with cADPR kcat/KM is about 20-200fold larger than for any other substrate
F37A/L196F/V252A/C253G
site-directed mutagenesis, the quadruple mutant shows detrimental effects of the V252A substitution on the efficiency with ADP-ribose, CDP-choline and 2',3'-cAMP (1.1-2.8fold decrease) while it increases 2fold the efficiency with cADPR. F37A/L196F/V252A/C253G-ADPRibase-Mn displays substrate efficiency ratios highly
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant GST-tagged wild-type and mutant enzymes from Escherichia coli strain BL21 by glutathione affinity chromatography, proteolytic tag cleavage
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ADPRM, cloned from liver, recombinant expression of GST-tagged wild-type and mutant enzymes in Escherichia coli strain BL21
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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 (W0NWJ0), Homo sapiens
Ribeiro, J.M.; Canales, J.; Cabezas, A.; Rodrigues, J.R.; Pinto, R.M.; Lopez-Villamizar, I.; Costas, M.J.; Cameselle, J.C.
Specific cyclic ADP-ribose phosphohydrolase obtained by mutagenic engineering of Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatase
Sci. Rep.
8
1036
2018
Homo sapiens (Q3LIE5)
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Release 2023.1 (January 2023)
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