BRENDA - Enzyme Database
show all sequences of 3.2.2.6

Probing the catalytic mechanism of bovine CD38/NAD+ glycohydrolase by site directed mutagenesis of key active site residues

Kuhn, I.; Kellenberger, E.; Cakir-Kiefer, C.; Muller-Steffner, H.; Schuber, F.; Biochim. Biophys. Acta 1844, 1317-1331 (2014)

Data extracted from this reference:

Engineering
Amino acid exchange
Commentary
Organism
D147A
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
E138A
site-directed mutagenesis, the mutation causes a modest increase in the rate of NAD+ transformation which is proportional to its concentration. At 4.0 M, the rate increase is about 1.2fold and the formation of beta-1'-O-methyl ADP-ribose amounts to about 80% of the total reaction products. The observed selectivity in favor of methanolysis is similar to that of wild-type enzyme. The ADP-ribosyl cyclase activity of E138A mutant is more affected by the competing nucleophile, i.e. formation of ADP-ribose and cADPR are reduced by 75% and 90% respectively at 4.0 M methanol, the mutant shows an increase in ADP cyclization and higly reduced overall activity compared to the wild-type enzyme
Bos taurus
E138Q
site-directed mutagenesis, in the presence of methanol, mutant E138Q efficiently catalyzes the formation of beta-1'-O-methyl ADP-ribose. But in contrast with mutant E138A, and like the wild-type enzyme, solvolysis does not affect the overall turnover rate of NAD+ indicating that the formation of the E.ADP-ribosyl intermediate is still rate limiting
Bos taurus
E218A
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
E218Q
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W118A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate compared to the wild-type enzyme
Bos taurus
W118A/W181A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate which is 16fold lower than the product of the effects of the two single mutations
Bos taurus
W118F
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W118H
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W181A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate and a reduced sensitivity to nicotinamide inhibition compared to the wild-type enzyme
Bos taurus
W181F
site-directed mutagenesis, the mutant shows a decrease in activity and an increase in ADP cyclization compared to the wild-type enzyme
Bos taurus
Inhibitors
Inhibitors
Commentary
Organism
Structure
1,N6-etheno NAD+
-
Bos taurus
2'-deoxy-2'-beta-D-fluoroarabinofuranoside NAD+
-
Bos taurus
2'-deoxy-2'-beta-D-fluororibofuranoside NAD+
non-covalent complex of the inhibitor formed with enzyme mutant E218Q, PDB ID: 3ghh, and with wild-type enzyme, PDB ID: 3kou
Bos taurus
3-aminopyridine
-
Bos taurus
Isonicotinic acid hydrazide
-
Bos taurus
nicotinamide
inhibition involves enzyme residue Trp181
Bos taurus
Pyridine
non-competitive inhibition of mutant E218A by pyridine
Bos taurus
KM Value [mM]
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
0.0171
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
0.0175
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
0.0189
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
0.0215
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
0.0247
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
0.0276
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
0.028
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
0.0289
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
0.0295
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
0.0297
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.036
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
0.0453
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
Natural Substrates/ Products (Substrates)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
NAD+ + H2O
Bos taurus
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
ADP-D-ribose + nicotinamide
-
-
?
Organism
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
Bos taurus
Q9TTF5
-
-
Reaction
Reaction
Commentary
Organism
NAD+ + H2O = ADP-D-ribose + nicotinamide
substrate binding with a crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD+, stepwise ordered uni-bi kinetic mechanism, overview. Residues Trp118, Glu138, Asp147, Trp181 stabilize the ribooxocarbenium ion-like transition state mostly by electrostatic interactions
Bos taurus
Substrates and Products (Substrate)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
additional information
selectivity in favor of methanolysis by wild-type enzyme and mutant E138A. 1'-Azido ADP-ribose is the reaction product obtained in the presence of azide. the ADP-ribosyl cyclase activity of wild-type bCD38 isminimal
731357
Bos taurus
?
-
-
-
-
NAD+ + H2O
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
731357
Bos taurus
ADP-D-ribose + nicotinamide
-
-
-
?
NAD+ + H2O
via a stepwise reaction mechanism
731357
Bos taurus
ADP-D-ribose + nicotinamide
-
-
-
?
Temperature Optimum [C]
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
37
-
assay at
Bos taurus
Turnover Number [1/s]
Turnover Number Minimum [1/s]
Turnover Number Maximum [1/s]
Substrate
Commentary
Organism
Structure
0.0155
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
0.016
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.03
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
0.122
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
0.49
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
0.81
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
3.5
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
6.64
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
7.8
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
10.36
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
18.37
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
57.9
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
pH Optimum
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
7.4
-
assay at
Bos taurus
Engineering (protein specific)
Amino acid exchange
Commentary
Organism
D147A
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
E138A
site-directed mutagenesis, the mutation causes a modest increase in the rate of NAD+ transformation which is proportional to its concentration. At 4.0 M, the rate increase is about 1.2fold and the formation of beta-1'-O-methyl ADP-ribose amounts to about 80% of the total reaction products. The observed selectivity in favor of methanolysis is similar to that of wild-type enzyme. The ADP-ribosyl cyclase activity of E138A mutant is more affected by the competing nucleophile, i.e. formation of ADP-ribose and cADPR are reduced by 75% and 90% respectively at 4.0 M methanol, the mutant shows an increase in ADP cyclization and higly reduced overall activity compared to the wild-type enzyme
Bos taurus
E138Q
site-directed mutagenesis, in the presence of methanol, mutant E138Q efficiently catalyzes the formation of beta-1'-O-methyl ADP-ribose. But in contrast with mutant E138A, and like the wild-type enzyme, solvolysis does not affect the overall turnover rate of NAD+ indicating that the formation of the E.ADP-ribosyl intermediate is still rate limiting
Bos taurus
E218A
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
E218Q
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W118A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate compared to the wild-type enzyme
Bos taurus
W118A/W181A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate which is 16fold lower than the product of the effects of the two single mutations
Bos taurus
W118F
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W118H
site-directed mutagenesis, the mutant shows a decrease in activity compared to the wild-type enzyme
Bos taurus
W181A
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate and a reduced sensitivity to nicotinamide inhibition compared to the wild-type enzyme
Bos taurus
W181F
site-directed mutagenesis, the mutant shows a decrease in activity and an increase in ADP cyclization compared to the wild-type enzyme
Bos taurus
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
1,N6-etheno NAD+
-
Bos taurus
2'-deoxy-2'-beta-D-fluoroarabinofuranoside NAD+
-
Bos taurus
2'-deoxy-2'-beta-D-fluororibofuranoside NAD+
non-covalent complex of the inhibitor formed with enzyme mutant E218Q, PDB ID: 3ghh, and with wild-type enzyme, PDB ID: 3kou
Bos taurus
3-aminopyridine
-
Bos taurus
Isonicotinic acid hydrazide
-
Bos taurus
nicotinamide
inhibition involves enzyme residue Trp181
Bos taurus
Pyridine
non-competitive inhibition of mutant E218A by pyridine
Bos taurus
KM Value [mM] (protein specific)
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
0.0171
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
0.0175
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
0.0189
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
0.0215
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
0.0247
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
0.0276
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
0.028
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
0.0289
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
0.0295
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
0.0297
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.036
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
0.0453
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
Natural Substrates/ Products (Substrates) (protein specific)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
NAD+ + H2O
Bos taurus
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
ADP-D-ribose + nicotinamide
-
-
?
Substrates and Products (Substrate) (protein specific)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
additional information
selectivity in favor of methanolysis by wild-type enzyme and mutant E138A. 1'-Azido ADP-ribose is the reaction product obtained in the presence of azide. the ADP-ribosyl cyclase activity of wild-type bCD38 isminimal
731357
Bos taurus
?
-
-
-
-
NAD+ + H2O
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
731357
Bos taurus
ADP-D-ribose + nicotinamide
-
-
-
?
NAD+ + H2O
via a stepwise reaction mechanism
731357
Bos taurus
ADP-D-ribose + nicotinamide
-
-
-
?
Temperature Optimum [C] (protein specific)
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
37
-
assay at
Bos taurus
Turnover Number [1/s] (protein specific)
Turnover Number Minimum [1/s]
Turnover Number Maximum [1/s]
Substrate
Commentary
Organism
Structure
0.0155
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
0.016
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.03
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
0.122
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
0.49
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
0.81
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
3.5
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
6.64
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
7.8
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
10.36
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
18.37
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
57.9
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
pH Optimum (protein specific)
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
7.4
-
assay at
Bos taurus
General Information
General Information
Commentary
Organism
additional information
structure-function analysis, overview. The enzyme catalyzes the formation of beta-1'-O-methyl ADP-ribose in presence of methanol, solvolysis does not affect the overall turnover rate of NAD+ by the wild-type enzyme. Precise role of key conserved active site residues Trp118, Glu138, Asp147, Trp181 and Glu218, effects of experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. Binding of 2'-fluorinated analogs of NAD+ and trappping of the reaction intermediate, detailed overview. Catalytic residue Glu138 is part of the TLEDTL signature domain, Asp147 is a highly conserved residue in the enzyme and is important for the catalytic parameters. Cooperative contribution of Trp118 and Trp181 to catalysis
Bos taurus
General Information (protein specific)
General Information
Commentary
Organism
additional information
structure-function analysis, overview. The enzyme catalyzes the formation of beta-1'-O-methyl ADP-ribose in presence of methanol, solvolysis does not affect the overall turnover rate of NAD+ by the wild-type enzyme. Precise role of key conserved active site residues Trp118, Glu138, Asp147, Trp181 and Glu218, effects of experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. Binding of 2'-fluorinated analogs of NAD+ and trappping of the reaction intermediate, detailed overview. Catalytic residue Glu138 is part of the TLEDTL signature domain, Asp147 is a highly conserved residue in the enzyme and is important for the catalytic parameters. Cooperative contribution of Trp118 and Trp181 to catalysis
Bos taurus
KCat/KM [mM/s]
kcat/KM Value [1/mMs-1]
kcat/KM Value Maximum [1/mMs-1]
Substrate
Commentary
Organism
Structure
0.54
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.55
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
1.21
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
6.4
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
10.8
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
29.3
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
200
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
220
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
290
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
360
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
630
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
3380
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
KCat/KM [mM/s] (protein specific)
KCat/KM Value [1/mMs-1]
KCat/KM Value Maximum [1/mMs-1]
Substrate
Commentary
Organism
Structure
0.54
-
NAD+
recombinant mutant W118A/W181A, pH 7.4, 37C
Bos taurus
0.55
-
NAD+
recombinant mutant E218A, pH 7.4, 37C
Bos taurus
1.21
-
NAD+
recombinant mutant E218Q, pH 7.4, 37C
Bos taurus
6.4
-
NAD+
recombinant mutant W118A, pH 7.4, 37C
Bos taurus
10.8
-
NAD+
recombinant mutant W181A, pH 7.4, 37C
Bos taurus
29.3
-
NAD+
recombinant mutant E138A, pH 7.4, 37C
Bos taurus
200
-
NAD+
recombinant mutant D147A, pH 7.4, 37C
Bos taurus
220
-
NAD+
recombinant mutant E138Q, pH 7.4, 37C
Bos taurus
290
-
NAD+
recombinant mutant W118F, pH 7.4, 37C
Bos taurus
360
-
NAD+
recombinant mutant W181F, pH 7.4, 37C
Bos taurus
630
-
NAD+
recombinant mutant W118H, pH 7.4, 37C
Bos taurus
3380
-
NAD+
recombinant wild-type enzyme, pH 7.4, 37C
Bos taurus
Other publictions for EC 3.2.2.6
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Temperature Optimum [C]
Temperature Range [C]
Temperature Stability [C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [C] (protein specific)
Temperature Range [C] (protein specific)
Temperature Stability [C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
749830
Chini
The NADase CD38 is induced by ...
Homo sapiens
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513
486-493
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-
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-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
1
-
-
750282
Shu
Blockade of CD38 diminishes l ...
Mus musculus
Cell. Signal.
42
249-258
2018
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
1
-
-
731357
Kuhn
Probing the catalytic mechanis ...
Bos taurus
Biochim. Biophys. Acta
1844
1317-1331
2014
-
-
-
-
11
-
7
12
-
-
-
1
-
2
-
-
-
1
-
-
-
-
3
-
1
-
-
12
1
-
-
-
-
-
-
-
-
-
-
-
11
-
-
7
-
12
-
-
-
1
-
-
-
-
-
-
-
-
3
-
1
-
-
12
1
-
-
-
-
1
1
-
12
12
731882
Ma
Basal CD38/cyclic ADP-ribose-d ...
Mus musculus
Glia
62
943-955
2014
-
-
-
-
-
-
-
-
-
-
-
4
-
1
-
-
-
-
-
4
-
-
4
-
1
-
-
-
1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4
-
-
-
-
-
4
-
-
4
-
1
-
-
-
1
-
-
-
-
2
2
-
-
-
731987
Shrimp
Revealing CD38 cellular locali ...
Homo sapiens
J. Am. Chem. Soc.
136
5656-5663
2014
-
-
-
-
2
-
-
-
2
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