Information on EC 2.3.1.117 - 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase

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The expected taxonomic range for this enzyme is: Bacteria

EC NUMBER
COMMENTARY hide
2.3.1.117
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RECOMMENDED NAME
GeneOntology No.
2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
succinyl-CoA + (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + H2O = CoA + N-succinyl-L-2-amino-6-oxoheptanedioate
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
L-lysine biosynthesis I
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Lysine biosynthesis
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lysine metabolism
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Metabolic pathways
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Microbial metabolism in diverse environments
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SYSTEMATIC NAME
IUBMB Comments
succinyl-CoA:(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
Involved in the biosynthesis of lysine in bacteria (including cyanobacteria) and higher plants. The 1992 edition of the Enzyme List erroneously gave the name 2,3,4,5-tetrahydropyridine-2-carboxylate N-succinyltransferase to this enzyme.
CAS REGISTRY NUMBER
COMMENTARY hide
88086-34-4
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
gene dapD
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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the DAP biosynthesis pathway is present in most Gram-negative bacteria and mycobacteria
metabolism
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tetrahydrodipicolinate N-succinyltransferase catalyses the transfer of the succinyl moiety of succinyl-CoA to the alpha-amino group of tetrahydrodipicolinate, the first committed step in the succinylase branch of the DAP biosynthesis pathway, diaminopimelic acid pathway of lysine biosynthesis, overview
physiological function
part of L-lysine biosynthetic pathway
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
succinyl-CoA + (2S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylic acid
CoA + (2S)-2-[(3-carboxypropanoyl)amino]-6-oxoheptanedioic acid
show the reaction diagram
succinyl-CoA + (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + H2O
CoA + N-succinyl-L-2-amino-6-oxoheptanedioate
show the reaction diagram
succinyl-CoA + 3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid
?
show the reaction diagram
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?
succinyl-CoA + 6-amino-2-hydroxypimelic acid
CoA + N-succinyl-6-amino-2-hydroxypimelate
show the reaction diagram
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?
succinyl-CoA + L-2-aminopimelate
CoA + N-succinyl-L-aminopimelate
show the reaction diagram
succinyl-CoA + L-6-amino-L-2-hydroxypimelic acid
CoA + N-succinyl-L-6-amino-L-2-hydroxypimelate
show the reaction diagram
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mixture of isomers
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?
succinyl-CoA + tetrahydrodipicolinate
?
show the reaction diagram
additional information
?
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no activity ith L-lysine, adipic acid, alpha-amino-adipic acid, L-epsilon-acetyl-lysine, L-glutamate, L-glutamine, L-norleucine, substrate specificity for DapD, overview. Binding of CoA to PaDapD does not induce any large conformational changes, ternary complex structure of DapD with bound CoA and succinate, overview
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
succinyl-CoA + (2S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylic acid
CoA + (2S)-2-[(3-carboxypropanoyl)amino]-6-oxoheptanedioic acid
show the reaction diagram
succinyl-CoA + (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + H2O
CoA + N-succinyl-L-2-amino-6-oxoheptanedioate
show the reaction diagram
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the enzyme is absolutely specific for the L-2-aminopimelate enantiomer
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
succinyl-CoA
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
slight increase of enzyme activity
Mn2+
slight increase of enzyme activity
Na+
stabilizes quartenary enzyme structure
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,6-dihydroxypimelic acid
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0.54 mM, 66% inhibition
2-Hydroxytetrahydropyran-2,6-dicarboxylic acid
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competitive inhibition
2-oxopimelic acid
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5 mM, 57% inhibition
4-oxo-(2E,5E)-heptadien-1,7-dioic acid
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0.5 mM, 32% inhibition
6-Aminocaproic acid
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5 mM, 35% inhibition
acetate
caused by inhibition of succinyl-CoA-binding or pH effect
CaCl2
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1 mM, 3% inhibition
Co2+
partial inhibition
CoCl2
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1 mM, 95% inhibition
CuSO4
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1 mM, complete loss of activity
D-2-aminopimelate
D-2-hydroxypimelic acid
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5 mM, 93% inhibition
DL-2-amino-5-thiapimelic acid
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5 mM, 75% inhibition
L-2-hydroxypimelic acid
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5 mM, 88% inhibition
MgCl2
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1 mM, 20% inhibition
MnCl2
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1 mM, 9% inhibition
N-ethylmaleimide
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16 mM, 42% inhibition
p-Chloromercuriphenylsulfonate
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0.16 mM, 97% inhibition
pimelic acid
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5 mM, 43% inhibition
Zn2+
1 mM, complete loss of enzyme acitivity
ZnCl2
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1 mM, 88% inhibition
additional information
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not inhibited by EDTA and Fe2+
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate
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pH 7.5, 22C
2
3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid
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1
L-2-aminopimelate
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0.015
succinyl-CoA
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0.02 - 0.022
tetrahydrodipicolinate
additional information
additional information
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reaction kinetics for DapD, overview
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000058
2-Hydroxytetrahydropyran-2,6-dicarboxylic acid
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0.31 - 0.76
D-2-aminopimelate
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
20
D-2-aminopimelate
Pseudomonas aeruginosa
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pH 7.5, 22C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 9
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50% of maximal activity at pH 7, 75% of maximal activity at pH 9.0
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
PDB
SCOP
CATH
ORGANISM
UNIPROT
Brucella suis biovar 1 (strain 1330)
Burkholderia pseudomallei (strain 1710b)
Campylobacter jejuni subsp. jejuni serotype O:2 (strain ATCC 700819 / NCTC 11168)
Corynebacterium glutamicum (strain ATCC 13032 / DSM 20300 / JCM 1318 / LMG 3730 / NCIMB 10025)
Corynebacterium glutamicum (strain ATCC 13032 / DSM 20300 / JCM 1318 / LMG 3730 / NCIMB 10025)
Corynebacterium glutamicum (strain ATCC 13032 / DSM 20300 / JCM 1318 / LMG 3730 / NCIMB 10025)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Unknown prokaryotic organism
Unknown prokaryotic organism
Unknown prokaryotic organism
Unknown prokaryotic organism
Unknown prokaryotic organism
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
68000
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gel filtration
72000
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sucrose density gradient centrifugation
100000
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gel filtration, homotrimer
110000
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recombinant DapD, gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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2 * 31000, SDS-PAGE
homotrimer
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gel filtration
trimer
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structure of DapD from Escherichia coli at 2.0 A resolution is shown. Comparison of the structure with the homologous enzyme from Mycobacterium bovis reveals the C-terminal helix undergoes a large rearrangement upon substrate binding, which contributes to cooperativity in substrate binding
crystal structure in complex with L-2-aminopimelate/coenzyme A and L-2-amino-6-oxopimelate/coenzyme A at 2.0 A resolution, hanging drop vapor diffusion from solutions of 10-13% poly(ethylene glycol) 4000, 94 mM MES, pH 6.4, 94 mM ammonium sulfate, and 4.7% 2-propanol in the presence of 16 mM (D,L)-2-aminopimelate and 2.5 mM CoA
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crystal structure of the enzyme in ternary complexes with pimelate/succinyl-CoA and L-2-aminopimelate with the nonreactive cofactor analog succinamide-CoA, 2.3 and 2.0 A resolution, crystals are prepared by cocrystallization using the hanging drop vapor diffusion method, drops are formed by mixing 0.005 ml 27 mg/ml enzyme with an equal volume of 17% poly(ethylene glycol) 4000, 188 mM ammonium sulfate, 94 mM MES, pH 6.4, 4.7% 2-propanol, 20 mM pimelate, and 5 mM succinyl-CoA or 5 mM succinamide-CoA
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crystallized from solutions of 16% poly(ethylene glycol) 4000, 200 mM ammonium sulfate, 100 mM HEPES, pH 7.5, and 10% 2-propanol, crystals belong to space group P21, X-ray structure refined to 2.2 A resolution
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crystallized in the cubic space group I23 or I213. Diffraction data analysis indicates the presence of five molecules per asymmetric unit. Data exhibit icosahedral point-group symmetry. Enzyme might assembles into a 60-mer exhibiting 235 point-group symmetry and crystallizes as such in space group I23. In this case, the combination of crystallographic and noncrystallographic symmetry elements results in an arrangement of the icosahedrons in the cubic crystal with one pentamer in the asymmetric unit. Another explanation is that the packing of the molecules itself mimics icosahedral symmetry. In this case both space groups I23 and I213 would be possible
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purified recombinant His6-tagged DapD with bound L-2-aminopimelate and D-2-aminopimelate or in complex with CoA/succinate, hanging drop vapour diffusion method, mixing of 0.002 ml of 26 mg/ml protein in 25 mM Tris-HCl pH 8.0, and 150 mM NaCl, with or without 10-15 mM CoA, with 0.002 ml of reservoir solution containing 19-20% of PEG3350, 0.3-0.4 M succinate, pH 6.2, and equilibration against reservoir solution for 1-2 days, incubation of the enzyme with formyl-CoA leads to better crystals, soaking of apoenzyme crystals in solution containing L-2-aminopimelate and D-2-aminopimelate, the CoA-complex also contains a succinatemolecule bound next to the acceptor arm of the CoA in the active site cleft, X-ray diffraction structure determination and analysis at 1.8-2.95 A resolution, molecular replacement
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
purification has to be carried out at 0-4C
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4C, 0.001 M 2-mercaptoethanol, 80% remaining activity after 1 month
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4C, no 2-mercaptoethanol, 4 days, 80% loss of activity
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity and size-exclusion chromatography
MnCl2, ammonium sulfate, DEAE-cellulose, acid treatment, hydroxyapatite, phenyl-Sepharose, chromatofocusing
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recombinant enzyme
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recombinant His-tagged DapD from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, removal of te the N-terminal His6-tag by thrombin cleavage is not successful
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using affinity chromatography and gel filtration
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using Ni-NTA chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
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expressed in Escherichia coli as a His-tagged fusion protein
expression in Escherichia coli
gene dapD, phylogenetic tree, expression of His-tagged DapD in Escherichia coli strain BL21(DE3)
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overexpressed in Escherichia coli
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E199A
completely inactive mutant
G222P
completely inactive mutant
additional information
binary complex of Mtb-DapD and succinyl-CoA
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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DapA is not an optimal target for drug development against Pseudomonas aeruginosa
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