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(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
?
-
high stereospecificity
-
?
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
N-succinyl-DL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
N-succinyl-LL-2,6-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-diaminopimelate + H2O
?
-
-
-
-
?
N-succinyl-LL-diaminopimelic acid + H2O
?
-
-
-
-
?
additional information
?
-
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-DL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-DL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
a combination of different computational methods, such as protein-ligand docking, MD simulations, free-energy analysis with the MM-PBSA method, and hybrid QM/MM calculations, to provide a detailed account of the substrate binding and catalytic reaction in three important mutants of DapE and compared them to the action of the wt-DapE
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
a combination of different computational methods, such as protein-ligand docking, MD simulations, free-energy analysis with the MM-PBSA method, and hybrid QM/MM calculations, to provide a detailed account of the substrate binding and catalytic reaction in three important mutants of DapE and compared them to the action of the wt-DapE
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
i.e. N-succinyl-L,L-diaminopimelic acid
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
additional information
?
-
-
acetylornithine deacetylase, succinyldiaminopimelate desuccinylase and carboxypeptidase G2 are evolutionarily related
-
-
?
additional information
?
-
-
kinetic mechanism
-
-
?
additional information
?
-
-
structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis
-
-
?
additional information
?
-
-
kinetic mechanism
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
additional information
?
-
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl LL-diaminopimelic acid + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
i.e. N-succinyl-L,L-diaminopimelic acid
-
-
?
N-succinyl-LL-2,6-diaminoheptanedioate + H2O
succinate + LL-2,6-diaminoheptanedioate
-
-
-
?
additional information
?
-
-
acetylornithine deacetylase, succinyldiaminopimelate desuccinylase and carboxypeptidase G2 are evolutionarily related
-
-
?
additional information
?
-
-
kinetic mechanism
-
-
?
additional information
?
-
-
structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis
-
-
?
additional information
?
-
-
kinetic mechanism
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Cd2+
-
65% of activity with Zn2+
sulfate
in one of the monomers of the ZnZn_DapE structure, both of these residues form a charged dipole interaction with a sulfate ion, a possible mimic of the carboxylic group of the substrate
Co2+
-
required and most active as a cofactor
Co2+
-
125% of activity with Zn2+
Co2+
-
can substitute for Zn2+
Co2+
-
metal-dependent enzyme (Zn2+ or Co2+). Determination of metal stoichiometry by ICP-AES indicates one tightly bound metal ion, while sequence homologies suggest the presence of two metal binding sites
Co2+
EPR and MCD data indicate that the two Co(II) ions in DapE are antiferromagnetically coupled
Mn2+
-
required
Mn2+
-
20% of activity with Zn2+
Zn2+
-
required
Zn2+
-
modelling of binding structure, overview
Zn2+
required for activity, DapE has one or two zinc ions bound in the active site, the two forms show different activity, structures of monometalated and dimetalated forms, overview
Zn2+
-
the enzyme requires two Zn2+ ions. Each of the Zn(II) ions adopts a distorted tetrahedral geometry and is coordinated by one imidazole group, H67 for Zn1 and H349 for Zn2, and one carboxylate group, E163 for Zn1 and E135 for Zn2. Both Zn(II) ions are bridged by an additional carboxylate groups of residue D100 on one side and water/hydroxide on the opposite side, forming a (mu-aquo)(mu-carboxylato)dizinc(II) core with one terminal carboxylate and one histidine residue at each metal site
Zn2+
-
di-nuclear Zn2+ enzyme, the side chain of Asp100 bridges the two Zn centers of the enzyme
Zn2+
-
required, dinuclear Zn(II)-loaded enzyme, binding structure, overview
Zn2+
-
required, the enzyme binds two Zn(II) ions in non-interactive binding sites with Kd values for the first Zn(II) binding event of 0.0044 mM, whereas the observed Kd values for the second metal binding event in DapE is 0.0136 mM
Zn2+
dinuclear Zn(II) active site
Zn2+
-
metal-dependent enzyme (Zn2+ or Co2+). Determination of metal stoichiometry by ICP-AES indicates one tightly bound metal ion, while sequence homologies suggest the presence of two metal binding sites
Zn2+
two Zn metal centers are essential to the catalytic action of the DapE enzyme. His67, His349, and Glu134 residues in the active site
Zn2+
untreated enzyme contains 0.8 Zn2+ per monomer and was enzymatically active
Zn2+
-
the enzyme possesses a catalytic domain with a di-zinc active site
Zn2+
required, dinuclear Zn(II)-loaded enzyme, binding structure, overview
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(2-carboxyethyl)-phosphonic acid
-
slight inhibition
2-amino-6-[(2-methylpropanoyl)amino]heptanedioic acid
-
slight inhibition
3-mercaptobenzoic acid
-
-
4-sulfanylbutanoic acid
-
-
aceto-hydroxamic acid
-
slight inhibition
D,L-2,6-diaminoheptanedioate
-
competitive inhibitor
D,L-diaminopimelic acid
-
competitive
D-penicillamine
-
competitive
enalapril
-
maleate salt, slight inhibition
L,L-diaminopimelic acid
-
competitive
LL-2,6-Diaminoheptanedioate
-
competitive inhibitor
N-(benzyloxycarbonyl)hydroxylamine
-
slight inhibition
N-phenyl-thiourea
-
slight inhibition
phenylboronic acid
-
competitive
succinate
-
poor inhibitor
2-thiopheneboronic acid
-
noncompetitive
2-thiopheneboronic acid
22.3% inhibition at 10 mM, non-competitive inhibitor
EDTA
-
complete
L-captopril
-
-
L-captopril
99.96%, 26.67% and 23.34% inhibition at 10 mM, 3 mM, and 1 mM
L-captopril
competitive inhibitor
L-captopril
-
low-micromolar inhibitor, DapE is not the main target of L-captopril inhibition
L-Penicillamine
-
-
L-Penicillamine
1 mM, 79.41% inhibition
additional information
-
no or poor inhibition by butylboronic acid, 4-carboxyphenylboronic acid, and 3-carboxyphenylboronic acid
-
additional information
design of structure-based, catalytic inhibitors, overview
-
additional information
-
design of structure-based, catalytic inhibitors, overview
-
additional information
-
mono-N-acyl derivatives of 2,6-diaminopimelic acid are no effective N-succinyl-L,L-diaminopimelic acid desuccinylase inhibitors, overview. No inhibition by 2-amino-6-(butanoylamino)heptanedioic acid, 2-amino-6-[(2,2-dimethylpropanoyl)amino]heptanedioic acid, 2-amino-6-(pentanoylamino)heptanedioic acid, 2-amino-6-(benzoylamino)heptanedioic acid, 2-amino-6-[(4-carboxybutanoyl)amino]heptanedioic acid, 2-amino-6-[(4-carboxy-3-methylbutanoyl)amino]heptanedioic acid, 2-amino-6-[(4-carboxy-3,3-dimethylbutanoyl)amino]heptanedioic acid, 2-amino-6-[(4-carboxy-2,2,3,3-tetrafluorobutanoyl)amino]heptanedioic acid, 2-amino-6-[[(2E)-4-methoxy-4-oxobut-2-enoyl]amino]heptanedioic acid, 2-amino-6-[(3-ethoxy-3-oxopropanoyl)amino]heptanedioic acid, and 2-amino-6-[[(2R)-4-methoxy-2-methylpent-4-enoyl]amino]heptanedioic acid
-
additional information
Tanimoto-based similarity searching in the PubChem Database with DapE substrate N-succinyl-LL-2,6-diaminoheptanedioate as a query molecule, followed by fragment-based docking approach using GLIDE XP identifies two potential substrate-competitive small molecule inhibitors of DapE. These new molecules may provide a starting point to search for novel therapeutics
-
additional information
-
Tanimoto-based similarity searching in the PubChem Database with DapE substrate N-succinyl-LL-2,6-diaminoheptanedioate as a query molecule, followed by fragment-based docking approach using GLIDE XP identifies two potential substrate-competitive small molecule inhibitors of DapE. These new molecules may provide a starting point to search for novel therapeutics
-
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0.26 - 0.99
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
730
N-succinyl LL-diaminopimelic acid
pH not specified in the publication, temperature not specified in the publication
3.2
N-succinyl-DL-2,6-diaminoheptanedioate
-
in the presence of Zn2+
0.03109 - 4.7
N-succinyl-LL-2,6-diaminoheptanedioate
0.73 - 1.4
N-succinyl-LL-2,6-diaminopimelic acid
0.65 - 0.73
N-succinyl-LL-diaminopimelate
0.26
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, ZnCo-loaded enzyme
0.73
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, Zn-loaded enzyme
0.73
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, ZnZn-loaded enzyme
0.74
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, CoZn-loaded enzyme
0.99
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, Co-loaded enzyme
0.99
(2S,6S)-2-amino-6-[(3-carboxypropanoyl)amino]heptane-dioic acid
-
pH 7.5, 30°C, CoCo-loaded enzyme
0.03109
N-succinyl-LL-2,6-diaminoheptanedioate
pH 8.0, 37°C
0.8
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant wild-type enzyme
1.2
N-succinyl-LL-2,6-diaminoheptanedioate
pH 7.5, 25°C, recombinant enzyme
1.3
N-succinyl-LL-2,6-diaminoheptanedioate
-
in the presence of Zn2+
1.3
N-succinyl-LL-2,6-diaminoheptanedioate
-
37°C, pH 8.1
1.3
N-succinyl-LL-2,6-diaminoheptanedioate
-
25°C, pH 7.6, in the presence of Zn2+
1.5
N-succinyl-LL-2,6-diaminoheptanedioate
-
37°C, pH 8.1, in the presence of Co2+
1.6
N-succinyl-LL-2,6-diaminoheptanedioate
-
in the presence of Co2+
1.6
N-succinyl-LL-2,6-diaminoheptanedioate
-
25°C, pH 7.6, in the presence of Co2+
2.1
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant mutant T325A
3
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant mutant T325S
4.7
N-succinyl-LL-2,6-diaminoheptanedioate
-
in the presence of Co2+
0.73
N-succinyl-LL-2,6-diaminopimelic acid
-
pH 7.5, 30°C, wild-type enzyme
1.4
N-succinyl-LL-2,6-diaminopimelic acid
-
pH 7.5, 30°C, mutant H67A
0.65
N-succinyl-LL-diaminopimelate
-
mutant enzyme E134D at pH 7.5
0.73
N-succinyl-LL-diaminopimelate
-
wild type enzyme at pH 7.5
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
140
N-succinyl LL-diaminopimelic acid
pH not specified in the publication, temperature not specified in the publication
0.0555 - 370
N-succinyl-LL-2,6-diaminoheptanedioate
1.5 - 140
N-succinyl-LL-2,6-diaminopimelic acid
0.13 - 140
N-succinyl-LL-diaminopimelate
0.0555
N-succinyl-LL-2,6-diaminoheptanedioate
-
in the presence of zinc
2.9
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant mutant T325S
4
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant mutant T325A
4.85
N-succinyl-LL-2,6-diaminoheptanedioate
pH 8.0, 37°C
80
N-succinyl-LL-2,6-diaminoheptanedioate
pH 7.5, 25°C, recombinant enzyme
114
N-succinyl-LL-2,6-diaminoheptanedioate
-
pH 7.5, 25°C, recombinant enzyme
200
N-succinyl-LL-2,6-diaminoheptanedioate
-
25°C, pH 7.6, in the presence of Zn2+
370
N-succinyl-LL-2,6-diaminoheptanedioate
-
25°C, pH 7.6, in the presence of Co2+
1.5
N-succinyl-LL-2,6-diaminopimelic acid
-
pH 7.5, 30°C, mutant H67A
140
N-succinyl-LL-2,6-diaminopimelic acid
-
pH 7.5, 30°C, wild-type enzyme
0.13
N-succinyl-LL-diaminopimelate
-
mutant enzyme E134D at pH 7.5
140
N-succinyl-LL-diaminopimelate
-
wild type enzyme at pH 7.5
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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1.62
(2-carboxyethyl)-phosphonic acid
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
17
2-amino-6-[(2-methylpropanoyl)amino]heptanedioic acid
Haemophilus influenzae
-
pH 7.5, 25°C
0.092
2-thiopheneboronic acid
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
0.034
3-mercaptobenzoic acid
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
0.043
4-sulfanylbutanoic acid
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
1
aceto-hydroxamic acid
Haemophilus influenzae
-
above, pH not specified in the publication, temperature not specified in the publication
0.042
D-captopril
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
0.05
D-penicillamine
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
1
enalapril
Haemophilus influenzae
-
above, pH not specified in the publication, temperature not specified in the publication
0.0137
L-Penicillamine
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
1
N-(benzyloxycarbonyl)hydroxylamine
Haemophilus influenzae
-
above, pH not specified in the publication, temperature not specified in the publication
0.01
N-phenyl-thiourea
Haemophilus influenzae
-
above, pH not specified in the publication, temperature not specified in the publication
0.107
phenylboronic acid
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
0.0033
L-captopril
Salmonella enterica
-
pH and temperature not specified in the publication
0.0033
L-captopril
Haemophilus influenzae
-
pH not specified in the publication, temperature not specified in the publication
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Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
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evolution
-
the enzyme is composed of catalytic and dimerization domains, and belongs to the M20 peptidase family
evolution
the enzyme is composed of catalytic and dimerization domains, and belongs to the M20 peptidase family
malfunction
deletion of the DapE gene is lethal to Helicobacter pylori, since the organism has no alternative pathway for lysine biosynthesis
malfunction
-
deletion of the DapE gene is lethal to Helicobacter pylori, since the organism has no alternative pathway for lysine biosynthesis
-
metabolism
-
DapE is involved in the meso-diaminopimelate (mDAP)/lysine biosynthetic pathway
metabolism
DapE is involved in the meso-diaminopimelate, mDAP/lysine biosynthetic pathway
metabolism
the enzyme catalyzes the seventh reaction step of the succinyl pathway
metabolism
-
the enzyme is part of the lysine biosynthetic pathway which is indispensable for bacterial survival
physiological function
-
DapE is a critical bacterial enzyme for the construction of the bacterial cell wall.
physiological function
DapE is essential for cell growth and proliferation
physiological function
critical enzyme of the lysine biosynthetic pathway
physiological function
-
the enzyme is a constituent of the divisome through association with the Ter complex. The enzyme facilitates functional Z ring formation by strengthening the Ter signal via ZapB. DapE depends on ZapB to localize to the Z ring. DapE shows a strong interaction with ZapB and requires the presence of ZapB to exert its function in division
physiological function
-
critical enzyme of the lysine biosynthetic pathway
-
additional information
-
DapE residues H355 and H80 are active site ligands, divalent metal binding properties of co-catalytic metallohydrolase active site, overview. Three-dimensional homological structure molecular modeling of N-acetyl-L-ornithine deacetylase, EC 3.5.1.16, from Escherichia coli, using the X-ray crystal structure of the DapE from Haemophilus influenzae, PDB ID 3IC1, as template
additional information
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residues Arg178, Thr325, and Asn345 play a role in substrate identification and stabilization of the enzyme active site. The glycine rich loop, Gly322-Ser326, facilitates tight binding of the substrate in the enzyme active site. Computational structure modeling by quantum mechanics/molecular mechanics calculations using the enzyme crystal structure PDB ID 3IC1
additional information
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structural comparisons of wild-type and inactive monomeric DapE enzymes with other M20 peptidases, active site and zinc binding structure, molecular modeling and dynamics simulations, overview. The dimerization domain in DapE enzymes is required for catalysis. Removal of the dimerization domain increases the flexibility of a conserved active site loop that may provide critical interactions with the substrate
additional information
structural comparisons of wild-type and inactive monomeric DapE enzymes with other M20 peptidases, active site and zinc binding structure, molecular modeling and dynamics simulations, overview. The dimerization domain in DapE enzymes is required for catalysis. Removal of the dimerization domain increases the flexibility of a conserved active site loop that may provide critical interactions with the substrate
additional information
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structural comparisons of wild-type and inactive monomeric DapE enzymes with other M20 peptidases, active site and zinc binding structure, molecular modeling and dynamics simulations, overview. The dimerization domain in DapE enzymes is required for catalysis. Removal of the dimerization domain increases the flexibility of a conserved active site loop that may provide critical interactions with the substrate
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sitting nanodroplet vapor diffusion method, using 6 mM ZnCl2, 43.1% (w/v) polyethylene glycol 400, 0.2 M sodium chloride, 0.1 M sodium/potassium phosphate pH 6.4, at 20°C
crystal structure of the enzyme in complex with the products succinic acid and diaminopimelic acid, crystal structure is determined at 1.95 A
crystal structure, PDB ID 3IC1, analysis, comparison with the structure of N-acetyl-L-ornithine deacetylase, EC 3.5.1.16, overview
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purified recombinant wild-type and mutant G172D enzymes, apoform and Zn2+-bound enzyme, using 400 nl of a precipitant solution containing 0.2 M ammonium acetate, 0.1 M Bis-Tris, pH 5.5, 25% w/v PEG 3350, and 400 nl of 15 mg/ml of protein in crystallization buffer, with or without 1 mM ZnCl2, within 14 days, X-ray diffraction structure determination and analysis at 1.84 A resolution
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ultrapure recombinant DapE with one and two zinc ions bound in the active site, respectively, at 16°C, by vapor diffusion in hanging drops containing 1 ml of precipitant solution containing 1 M ammonium sulfate, 0.2 M NaCl, and 0.1 M Na acetate, pH 4.4, and 0.001 ml of 13 mg/ml of DapE with three equivalents of zinc, 2 weeks, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution
purified recombinant His-tagged enzyme, hanging drop vapour diffusion method, 0.001-0.002 ml of 3-7 mg/ml protein in 50 mM Bis-Tris, pH 6.0, 200 mM NaCl, 0.5 mM TCEP is mixed with 0.001-0.002 ml reservoir solution, containing 5-10% w/v PEG 4000 or PEG 3350, 35-120 mM ammonium sulfate, 100 mM sodium acetate, pH 4.1-4.6, and equilibrated against 0.9 ml reservoir solution, at room temperature, 1 day, method optimization, X-ray diffraction structure determination and analysis at 2.4-2.58 A resolution, two crystal forms
sitting-drop vapor-diffusion method at 16°C, three-dimensional X-ray crystal structure of the enzyme in complex with L-captopril at 1.8 A resolution
purified recombinant enzyme, apoform and Zn2+-bound enzyme, using 400 nl of a precipitant solution containing 20% v/v 1,4-butanediol, 0.1 M sodium acetate, pH 4.5, and 400 nl of 19 mg/ml protein in crystallization buffer, with or without 1 mM ZnCl2, within 14 days, X-ray diffraction structure determination and analysis at 1.65 A resolution
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E134A
-
Glu134 replaced by alanine
H67A/H349A
the proton transfer process is not possible in the mutant, the catalytic activities are effectively quenched (as determined by relaxed potential energy scan)
T325A
-
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
T325C
-
site-directed mutagenesis, inactive mutant
T325S
-
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type enzyme
E134D
-
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. In the case of E134D mutation, the shorter side chain length of the Asp residue at the 134 position (compared to Glu134 in the wild-type enzyme) makes the negatively charged carboxylate group of the Asp134 residue more distant from the negatively charged substrate, N-succinyl-LL-2,6-diaminoheptanedioate. In addition, the metal centers contribute more favorably toward the substrate binding in the E134D mutant as compared to that in wild-type enzyme, which indicates a stronger substrate binding with the metal centers in the mutant. The increased metal-substrate binding in the E134D mutant is a result of the shorter side chain of Asp134, which allows the negatively charged N-succinyl-LL-2,6-diaminoheptanedioate to come closer to the metal centers in E134D as compared to that in wild-type enzyme
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H349A
-
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant. The computed values of the free energy of substrate binding in this study suggest no substrate binding in the H349A mutant
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H67A
-
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant. The computed values of the free energy of substrate binding in this study suggest a less favorable substrate binding in the H67A mutant compared to wild-type enzyme
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H67A/H349A
-
the proton transfer process is not possible in the mutant, the catalytic activities are effectively quenched (as determined by relaxed potential energy scan)
-
E134D
-
Glu134 replaced by aspartate
E134D
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. In the case of E134D mutation, the shorter side chain length of the Asp residue at the 134 position (compared to Glu134 in the wild-type enzyme) makes the negatively charged carboxylate group of the Asp134 residue more distant from the negatively charged substrate, N-succinyl-LL-2,6-diaminoheptanedioate. In addition, the metal centers contribute more favorably toward the substrate binding in the E134D mutant as compared to that in wild-type enzyme, which indicates a stronger substrate binding with the metal centers in the mutant. The increased metal-substrate binding in the E134D mutant is a result of the shorter side chain of Asp134, which allows the negatively charged N-succinyl-LL-2,6-diaminoheptanedioate to come closer to the metal centers in E134D as compared to that in wild-type enzyme
H349A
-
site-directed mutagenesis, inactive mutant
H349A
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant. The computed values of the free energy of substrate binding in this study suggest no substrate binding in the H349A mutant
H67A
-
site-directed mutagenesis, the mutant shows 180fold decreased activity compred to the wild-type enzyme. Approximately 70% of the maximal catalytic activity is recovered after the addition of 1 equiv of Zn2+
H67A
the free energy of substrate binding in the mutant enzyme is compared with the substrate binding free energy in the wild-type enzyme. Compared to wild-type enzyme, a relatively weaker substrate binding is observed in the histidine mutant. The computed values of the free energy of substrate binding in this study suggest a less favorable substrate binding in the H67A mutant compared to wild-type enzyme
additional information
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construction of dimerization domain deletion mutants, that all show no activity
additional information
construction of dimerization domain deletion mutants, that all show no activity
additional information
-
construction of dimerization domain deletion mutants, that all show no activity
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Boyen, A.; Charlier, D.; Charlier, J.; Sakanyan, V.; Mett, I.; Glansdorff, N.
Acetylornithine deacetylase, succinyldiaminopimelate desuccinylase and carboxypeptidase G2 are evolutionarily related
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Hydrolysis of N-succinyl-L,L-diaminopimelic acid by Haemophilus influenzae dapE-encoded desuccinylase: metal activation, solvent isotope effects, and kinetic mechanism
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Haemophilus influenzae, Haemophilus influenzae RD
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Substrate specificity, metal binding properties, and spectroscopic characterization of the DapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Haemophilus influenzae
Biochemistry
42
10756-10763
2003
Haemophilus influenzae
brenda
Davis, R.; Bienvenue, D.; Swierczek, S.I.; Gilner, D.M.; Rajagopal, L.; Bennett, B.; Holz, R.C.
Kinetic and spectroscopic characterization of the E134A- and E134D-altered dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Haemophilus influenzae
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11
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Proteomic analysis of antigens from Leishmania infantum promastigotes
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6
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Leishmania infantum
brenda
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Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity
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19
6350-6352
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Haemophilus influenzae
brenda
Gillner, D.; Bienvenue, D.; Nocek, B.; Joachimiak, A.; Zachary, V.; Bennett, B.; Holz, R.
The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Haemophilus influenzae contains two active-site histidine residues
J. Biol. Inorg. Chem.
14
1-10
2009
Haemophilus influenzae
brenda
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Structural basis for catalysis by the mono- and dimetalated forms of the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase
J. Mol. Biol.
397
617-626
2010
Haemophilus influenzae (P44514), Haemophilus influenzae
brenda
Brunger, A.T.; Das, D.; Deacon, A.M.; Grant, J.; Terwilliger, T.C.; Read, R.J.; Adams, P.D.; Levitt, M.; Schroeder, G.F.
Application of DEN refinement and automated model building to a difficult case of molecular-replacement phasing: the structure of a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum
Acta Crystallogr. Sect. D
68
391-403
2012
Corynebacterium glutamicum (Q59284), Corynebacterium glutamicum, Corynebacterium glutamicum DSM 20300 (Q59284)
brenda
Uda, N.R.; Creus, M.
Selectivity of inhibition of N-succinyl-L,L-diaminopimelic acid desuccinylase in bacteria: the product of dapE-gene is not the target of L-captopril antimicrobial activity
Bioinorg. Chem. Appl.
2011
306465
2011
Salmonella enterica
brenda
Reinhard, L.; Mueller-Dieckmann, J.; Weiss, M.S.
Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of succinyl-diaminopimelate desuccinylase (Rv1202, DapE) from Mycobacterium tuberculosis
Acta Crystallogr. Sect. F
68
1089-1093
2012
Mycobacterium tuberculosis (P9WHS9), Mycobacterium tuberculosis
brenda
Hlavacek, J.; Vitovcova, M.; Sazelova, P.; Picha, J.; Vanek, V.; Budesinsky, M.; Jiracek, J.; Gillner, D.M.; Holz, R.C.; Miksik, I.; Kasicka, V.
Mono-N-acyl-2,6-diaminopimelic acid derivatives: analysis by electromigration and spectroscopic methods and examination of enzyme inhibitory activity
Anal. Biochem.
467
4-13
2014
Haemophilus influenzae
brenda
Dutta, D.; Mishra, S.
The structural and energetic aspects of substrate binding and the mechanism of action of the DapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) investigated using a hybrid QM/MM method
Phys. Chem. Chem. Phys.
16
26348-26358
2014
Haemophilus influenzae
brenda
Nocek, B.; Starus, A.; Makowska-Grzyska, M.; Gutierrez, B.; Sanchez, S.; Jedrzejczak, R.; Mack, J.C.; Olsen, K.W.; Joachimiak, A.; Holz, R.C.
The dimerization domain in DapE enzymes is required for catalysis
PLoS ONE
9
e93593
2014
Haemophilus influenzae, Vibrio cholerae (Q9KQ52), Vibrio cholerae
brenda
McGregor, W.C.; Gillner, D.M.; Swierczek, S.I.; Liu, D.; Holz, R.C.
Identification of a histidine metal ligand in the argE-encoded N-acetyl-L-ornithine deacetylase from Escherichia coli
SpringerPlus
2
482
2013
Haemophilus influenzae
brenda
Starus, A.; Nocek, B.; Bennett, B.; Larrabee, J.A.; Shaw, D.L.; Sae-Lee, W.; Russo, M.T.; Gillner, D.M.; Makowska-Grzyska, M.; Joachimiak, A.; Holz, R.C.
Inhibition of the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis by L-captopril
Biochemistry
54
4834-4844
2015
Neisseria meningitidis (Q9JYL2), Neisseria meningitidis, Neisseria meningitidis MC58 (Q9JYL2)
brenda
Nocek, B.; Reidl, C.; Starus, A.; Heath, T.; Bienvenue, D.; Osipiuk, J.; Jedrzejczak, R.; Joachimiak, A.; Becker, D.P.; Holz, R.C.
Structural evidence of a major conformational change triggered by substrate binding in DapE enzymes impact on the catalytic mechanism
Biochemistry
57
574-584
2018
Haemophilus influenzae (P44514), Haemophilus influenzae, Haemophilus influenzae ATCC 51907 (P44514)
brenda
Mandal, R.; Das, S.
In silico approach towards identification of potential inhibitors of Helicobacter pylori DapE
J. Biomol. Struct. Dyn.
33
1460-1473
2015
Helicobacter pylori (O25002), Helicobacter pylori, Helicobacter pylori ATCC 700392 (O25002)
brenda
Dutta, D.; Mishra, S.
Loss of catalytic activity in the E134D, H67A, and H349A mutants of DapE mechanistic analysis with QM/MM investigation
J. Phys. Chem. B
120
11654-11664
2016
Haemophilus influenzae (P44514), Haemophilus influenzae ATCC 51907 (P44514)
brenda
Du, S.; Lutkenhaus, J.
The N-succinyl-L,L-diaminopimelic acid desuccinylase DapE acts through ZapB to promote septum formation in Escherichia coli
Mol. Microbiol.
105
326-345
2017
Escherichia coli
brenda
Heath, T.K.; Lutz, M.R.; Reidl, C.T.; Guzman, E.R.; Herbert, C.A.; Nocek, B.P.; Holz, R.C.; Olsen, K.W.; Ballicora, M.A.; Becker, D.P.
Practical spectrophotometric assay for the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase, a potential antibiotic target
PLoS ONE
13
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2018
Haemophilus influenzae
brenda
Usha, V.; Lloyd, A.J.; Roper, D.I.; Dowson, C.G.; Kozlov, G.; Gehring, K.; Chauhan, S.; Imam, H.T.; Blindauer, C.A.; Besra, G.S.
Reconstruction of diaminopimelic acid biosynthesis allows characterisation of Mycobacterium tuberculosis N-succinyl-L,L-diaminopimelic acid desuccinylase
Sci. Rep.
6
23191
2016
Mycobacterium tuberculosis (P9WHS9), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WHS9)
brenda