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Information on EC 4.3.3.7 - 4-hydroxy-tetrahydrodipicolinate synthase and Organism(s) Corynebacterium glutamicum and UniProt Accession P19808

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EC Tree
     4 Lyases
         4.3 Carbon-nitrogen lyases
             4.3.3 Amine-lyases
                4.3.3.7 4-hydroxy-tetrahydrodipicolinate synthase
IUBMB Comments
The reaction can be divided into three consecutive steps: Schiff base formation with pyruvate, the addition of L-aspartate-semialdehyde, and finally transimination leading to cyclization with simultaneous dissociation of the product. The product of the enzyme was initially thought to be (S)-2,3-dihydrodipicolinate [1,2], and the enzyme was classified accordingly as EC 4.2.1.52, dihydrodipicolinate synthase. Later studies of the enzyme from the bacterium Escherichia coli have suggested that the actual product of the enzyme is (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate , and thus the enzyme has been reclassified as 4-hydroxy-tetrahydrodipicolinate synthase. However, the identity of the product is still controversial, as more recently it has been suggested that it may be (S)-2,3-dihydrodipicolinate after all .
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Corynebacterium glutamicum
UNIPROT: P19808
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Word Map
The taxonomic range for the selected organisms is: Corynebacterium glutamicum
The enzyme appears in selected viruses and cellular organisms
Synonyms
dhdps, dihydrodipicolinate synthase, dhdps2, pa1010, dihydrodipicolinic acid synthase, cjdhdps, cdhdps, 4-hydroxy-tetrahydrodipicolinate synthase, mrsa-dhdps, dhdpa synthase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
DHDPS
dihydrodipicolinate synthase
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dihydrodipicolinic acid synthase
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dihydropicolinate synthetase
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pyruvate-aspartic semialdehyde condensing enzyme
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synthase, dihydrodipicolinate
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VEG81
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Vegetative protein 81
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
elimination
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SYSTEMATIC NAME
IUBMB Comments
L-aspartate-4-semialdehyde hydro-lyase [adding pyruvate and cyclizing; (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate-forming]
The reaction can be divided into three consecutive steps: Schiff base formation with pyruvate, the addition of L-aspartate-semialdehyde, and finally transimination leading to cyclization with simultaneous dissociation of the product. The product of the enzyme was initially thought to be (S)-2,3-dihydrodipicolinate [1,2], and the enzyme was classified accordingly as EC 4.2.1.52, dihydrodipicolinate synthase. Later studies of the enzyme from the bacterium Escherichia coli have suggested that the actual product of the enzyme is (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate [3], and thus the enzyme has been reclassified as 4-hydroxy-tetrahydrodipicolinate synthase. However, the identity of the product is still controversial, as more recently it has been suggested that it may be (S)-2,3-dihydrodipicolinate after all [5].
CAS REGISTRY NUMBER
COMMENTARY hide
9055-59-8
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
L-aspartate 4-semialdehyde + pyruvate
dihydrodipicolinate + H2O
show the reaction diagram
lysine insensitivity of dihydrodipicolinate synthase analyzed, catalytic lysine residue forms a Schiff base adduct with pyruvate, active site lysine residues (K176a, K176b)
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?
(S)-aspartate-4-semialdehyde + pyruvate
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinic acid + H2O
show the reaction diagram
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?
L-aspartate-4-semialdehyde + pyruvate
dihydrodipicolinate + H2O
show the reaction diagram
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(S)-aspartate-4-semialdehyde + pyruvate
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinic acid + H2O
show the reaction diagram
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3-Bromopyruvate
competitive inhibition, pyruvate as varied substrate
L-aspartate
competitive inhibition, L-aspartate 4-semialdehyde as varied substrate
L-aspartate 4-semialdehyde
uncompetitive inhibition by high concentrations of, no overcome by increasing pyruvate concentrations from 5 to 15 mM
L-lysine
lack of feedback inhibition, not regulated under normal physiological conditions
oxaloacetate
non-competitive inhibition, pyruvate as varied substrate
Succinic semialdehyde
uncompetitive inhibition, L-aspartate 4-semialdehyde as varied substrate
additional information
-
no feedback inhibition by L-lysine
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
L-lysine
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mutagenesis of the lysine binding sites of the Corynebacterium glutamicum enzyme according to the residues in the Escherichia coli enzyme does not conver the expected feedback inhibition but an activation of the enzyme by L-lysine
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.63
L-aspartate 4-semialdehyde
reaction mixture includes 100 mM Tris-HCl, 2.5 mM pyruvate, 0.05-0.1 microg dihydrodipicolinate synthase and 0.2 mM NADPH, from 5.6 to 22.4 mM plots deviate from typical Michaelis-Menten kinetics, increased concentration fits an uncompetitive substrate inhibition model
0.32
pyruvate
2.5 mM pyruvate replaced by 0.1-2 mM, no substrate inhibition observed at high concentrations of pyruvate
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
213
L-aspartate 4-semialdehyde
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
660
L-lysine
Corynebacterium glutamicum
5 mM pyruvate, addition of 0-716 mM lysine, lack of feedback inhibition
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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structure comparison with the enzyme from Escherichia coli
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
158000
native protein, gel filtration, homotetramer predicted
73000
approximating the size of two DHDPS proteins interacting to form a dimer
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homotetramer
ribbons rendition of homotetramer in the crystal lattice shown
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop method, data collection and refinement statistics, refinement resolution originally extended to 3.0 A, gradually increased to 2.5 A, and finally to 2.2 A, structural similarities to other dihydrodipicolinate synthase
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K68H
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site-directed mutagenesis, the mutant is not inhibited by L-lysine
P61A/T63L
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site-directed mutagenesis, the mutant is not inhibited by L-lysine
P61A/T63L/A65H
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site-directed mutagenesis, the mutant is not inhibited by L-lysine
T63L
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site-directed mutagenesis, the mutant is not inhibited by L-lysine
T92E
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site-directed mutagenesis, the mutant is not inhibited by L-lysine
T96E
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site-directed mutagenesis, the mutant is not inhibited by L-lysine and shows reduced activity compared to the wild-type enzyme
T96E/K68H
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site-directed mutagenesis, the mutant is not inhibited by L-lysine and shows reduced activity compared to the wild-type enzyme
T96E/K68H/P61A/T63L
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site-directed mutagenesis, the mutant is activated by L-lysine 3fold shows reduced activity compared to the wild-type enzyme
T96E/K68H/P61A/T63L/A65H
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site-directed mutagenesis the mutant is activated by L-lysine 5fold shows reduced activity compared to the wild-type enzyme
T96E/K68H/T63L
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site-directed mutagenesis, the mutant is activated by L-lysine and shows reduced activity compared to the wild-type enzyme
additional information
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mutagenesis of the lysine binding sites of the Corynebacterium glutamicum enzyme according to the residues in the Escherichia coli enzyme does not conver the expected feedback inhibition but an activation of the nezyme by L-lysine
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
gel filtration, SDS-PAGE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli STBL2, pET23b vector
gene dapA, expression of wild-type and mutant enzymes in Escherichia coli strain BL21 (DE3)
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bonnassie, S.; Oreglia, J.; Sicard, A.M.
Nucleotide sequence of the dapA gene from Corynebacterium glutamicum
Nucleic Acids Res.
18
6421
1990
Corynebacterium glutamicum
Manually annotated by BRENDA team
Rice, E.A.; Bannon, G.A.; Glenn, K.C.; Jeong, S.S.; Sturman, E.J.; Rydel, T.J.
Characterization and crystal structure of lysine insensitive Corynebacterium glutamicum dihydrodipicolinate synthase (cDHDPS) protein
Arch. Biochem. Biophys.
480
111-121
2008
Corynebacterium glutamicum (P19808), Corynebacterium glutamicum
Manually annotated by BRENDA team
Geng, F.; Chen, Z.; Zheng, P.; Sun, J.; Zeng, A.
Exploring the allosteric mechanism of dihydrodipicolinate synthase by reverse engineering of the allosteric inhibitor binding sites and its application for lysine production
Appl. Microbiol. Biotechnol.
97
1963-1971
2012
Corynebacterium glutamicum, Corynebacterium glutamicum ATCC 13032, Escherichia coli, Escherichia coli MG1655
Manually annotated by BRENDA team