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Information on EC 1.17.1.8 - 4-hydroxy-tetrahydrodipicolinate reductase and Organism(s) Escherichia coli and UniProt Accession P04036

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IUBMB Comments
The substrate of the enzyme was initially thought to be (S)-2,3-dihydrodipicolinate , and the enzyme was classified accordingly as EC 1.3.1.26, dihydrodipicolinate reductase. Later studies of the enzyme from the bacterium Escherichia coli have suggested that the actual substrate of the enzyme is (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate, and that its activity includes a dehydration step , and thus the enzyme has been reclassified as 4-hydroxy-tetrahydrodipicolinate reductase. However, the identity of the substrate is still controversial, as more recently it has been suggested that it may be (S)-2,3-dihydrodipicolinate after all .
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Escherichia coli
UNIPROT: P04036
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The taxonomic range for the selected organisms is: Escherichia coli
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Synonyms
dihydrodipicolinate reductase, dhdpr, mrsa-dhdpr, dihydrodipicolinic acid reductase, abdhdpr, 4-hydroxy-tetrahydrodipicolinate reductase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dihydrodipicolinate reductase
-
dihydrodipicolinate reductase
-
-
dihydrodipicolinic acid reductase
-
-
-
-
reductase, dihydrodipicolinate
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NAD(P)+ + H2O = (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NAD(P)H + H+
show the reaction diagram
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NAD(P)+ + H2O = (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NAD(P)H + H+
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
-
-
-
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oxidation
-
-
-
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reduction
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-
SYSTEMATIC NAME
IUBMB Comments
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate:NAD(P)+ 4-oxidoreductase
The substrate of the enzyme was initially thought to be (S)-2,3-dihydrodipicolinate [1], and the enzyme was classified accordingly as EC 1.3.1.26, dihydrodipicolinate reductase. Later studies of the enzyme from the bacterium Escherichia coli have suggested that the actual substrate of the enzyme is (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate, and that its activity includes a dehydration step [2], and thus the enzyme has been reclassified as 4-hydroxy-tetrahydrodipicolinate reductase. However, the identity of the substrate is still controversial, as more recently it has been suggested that it may be (S)-2,3-dihydrodipicolinate after all [3].
CAS REGISTRY NUMBER
COMMENTARY hide
9055-46-3
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NAD(P)H + H+
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NAD(P)+ + H2O
show the reaction diagram
-
-
-
?
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NADH + H+
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NAD+ + H2O
show the reaction diagram
-
-
-
?
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NADPH + H+
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NADP+ + H2O
show the reaction diagram
-
-
-
?
2,3-dihydrodipicolinate + NAD(P)H
2,3,4,5-tetrahydrodipicolinate + NAD(P)+
show the reaction diagram
(4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate + NADPH + H+
?
show the reaction diagram
-
-
-
-
r
2,3-dihydrodipicolinate + 3'-NADPH + H+
2,3,4,5-tetrahydrodipicolinate + 3'-NADP+ + H2O
show the reaction diagram
-
-
-
-
r
2,3-dihydrodipicolinate + alpha-NADPH + H+
2,3,4,5-tetrahydrodipicolinate + alpha-NADP+ + H2O
show the reaction diagram
-
-
-
-
r
2,3-dihydrodipicolinate + NAD(P)H
2,3,4,5-tetrahydrodipicolinate + NAD(P)+
show the reaction diagram
2,3-dihydrodipicolinate + reduced 3-acetylpyridine adenine dinucleotide
2,3,4,5-tetrahydrodipicolinate + oxidized 3-acetylpyridine adenine dinucleotide
show the reaction diagram
-
-
-
?
2,3-dihydrodipicolinate + reduced 3-acetylpyridine adenine dinucleotide
2,3,4,5-tetrahydrodipicolinate + oxidized 3-acetylpyridine adenine dinucleotide + H2O
show the reaction diagram
-
-
-
-
r
2,3-dihydrodipicolinate + reduced nicotinamide hypoxanthine dinucleotide phosphate
2,3,4,5-tetrahydrodipicolinate + oxidized nicotinamide hypoxanthine dinucleotide phosphate + H2O
show the reaction diagram
-
-
-
-
r
2,3-dihydrodipicolinate + thio-NADPH + H+
2,3,4,5-tetrahydrodipicolinate + thio-NADP+ + H2O
show the reaction diagram
-
-
-
-
r
dihydrodipicolinate + NADH + H+
tetrahydrodipicolinate + NAD+
show the reaction diagram
-
substrate dihydrodipicolinate is instable
-
-
?
pyridine dicarboxylate + NADH + H+
reduced pyridine dicarboxylate + NAD+
show the reaction diagram
-
stable substrate analog, 25 mM phosphate D2O (deuterium water) buffer, pH 7.8 for NMR analysis of binding interactions with saturation transfer difference titration studies at 298 K (25°C)
-
-
?
additional information
?
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-
DHDPR accepts (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid as true substrate rather than dihydrodipicolinate, suggesting that DHDPR catalyzes an overall deoxygenation reaction, likely by a dehydratase-reductase route, substrate specificity, overview. A critical role is played by residue His 159 in the catalytic mechanism of DHDPR. Replacement of this residue with an alanine or a glutamine is reported to result in a 150-200fold reduction in catalytic rate as well as a 6fold increase in KM. His 159 has been proposed to act as a general acid during catalysis, providing the proton required after hydride addition. No activity with beta-hydroxypyruvate and 3-fluoropyruvate
-
-
?
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
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate + NAD(P)H + H+
(S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate + NAD(P)+ + H2O
show the reaction diagram
-
-
-
?
2,3-dihydrodipicolinate + NAD(P)H
2,3,4,5-tetrahydrodipicolinate + NAD(P)+
show the reaction diagram
2,3-dihydrodipicolinate + NAD(P)H
2,3,4,5-tetrahydrodipicolinate + NAD(P)+
show the reaction diagram
dihydrodipicolinate + NADH + H+
tetrahydrodipicolinate + NAD+
show the reaction diagram
-
substrate dihydrodipicolinate is instable
-
-
?
additional information
?
-
-
DHDPR accepts (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid as true substrate rather than dihydrodipicolinate, suggesting that DHDPR catalyzes an overall deoxygenation reaction, likely by a dehydratase-reductase route, substrate specificity, overview. A critical role is played by residue His 159 in the catalytic mechanism of DHDPR. Replacement of this residue with an alanine or a glutamine is reported to result in a 150-200fold reduction in catalytic rate as well as a 6fold increase in KM. His 159 has been proposed to act as a general acid during catalysis, providing the proton required after hydride addition. No activity with beta-hydroxypyruvate and 3-fluoropyruvate
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
NADPH
additional information
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,6-pyridinedicarboxylic acid
(4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate
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-
2,6-pyridine dicarboxylate
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stable analog of the dihydrodipicolinate substrate, the binding affinity is not affected by the presence of NADH or NAD+
2,6-pyridinedicarboxylic acid
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dead-end inhibitor
3-acetyl-NAD+
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alpha-picolinic acid
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-
catechol rhodanine acetic acid
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binds to the NADH cofactor site
DELTA3-tetrahydroisophthalic acid
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moderate inhibition
dipicolinate
isophthalic acid
NADP+
phosphate
-
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADPH
-
similar affinity as NADH
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.043
(2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate
histidine-tagged enzyme, pH and temperature not specified in the publication
0.529
(4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate
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-
0.05
2,3-dihydrodipicolinate
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-
0.08
3'-NADPH
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-
0.052
alpha-NADPH
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-
0.009
dihydrodipicolinate
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-
0.0016 - 0.0066
NADH
0.0056 - 0.0165
NADPH
0.004
reduced 3-acetylpyridine adenine dinucleotide
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-
0.009
reduced nicotinamide hypoxanthine dinucleotide phosphate
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-
-
0.0021
thio-NADPH
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-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.435
(4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinate
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-
0.33
2,6-pyridinedicarboxylic acid
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5.5 - 15
isophthalic acid
24
NADP+
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-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
135
-
purified enzyme
300
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purified enzyme
398
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purified enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8
-
dehydration assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 7.5
-
-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
additional information
-
NMR studies uncover that dihydrodipicolinate reductase is also a dehydratase, overview
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
28000
SDS-PAGE
110000
12000
-
gel filtration
28000
-
SDS-PAGE
28798
-
4 * 28798, nucleotide sequence
28820
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
x * 28000, SDS-PAGE
?
-
? * 28757-29000, SDS-PAGE and sequence determination
homotetramer
-
native state
tetramer
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapour diffusion method, crystal structure x-ray analysis and binding study with NADPH, NADH, 3-acetyl-NADH, and reduced nicotinamide hypoxanthine dinucleotide phosphate and other pyridine nucleotide derivatives in complex with the enzyme
R-factor 21.4%, three-dimensional structure analysis , homotetramer with 3 molecules of NADH, 3 molecules of inhibitor 2,6-pyridinedicarboxylic acid, 1 phosphate ion and 186 water molecules per asymmetric unit in the model
R-factor 18.6%, structure model of enzyme complexed with NADPH, analysis of cofactor binding site
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
70
-
3 min stable
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-15°C, several months
-
-20°C, 0.04 M Tris buffer, pH 8.1, precipitate in 65% w/v ammonium sulfate, several months
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
overexpression in Escherichia coli from plasmid
cells grown in M9 medium containing 2H, 15N, and 13C-labeled sources, collected, lysed, and protein purified with a QA52 anion exchange column and a Blue Trisacryl affinity column with gravity gradient chromatography, fractions with activity pooled and concentrated using an Amicon ultrafiltration device with YM10 membrane, desalted and loaded onto the Blue Trisacryl affinity column and eluted with a linear gradient of 0-2 M NaCl, 25 mM Tris buffer, pH 7.5, pooled, concentrated and buffer ecxchanged
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overexpression in Escherichia coli from plasmid
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protein is purified using a QA52 anion exchange column and a Blue Trisacryl affinity column with gravity gradient chromatography
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purified from wild-type
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
dapB gene, overexpression from plasmid in Escherichia coli
expression of the histidine-tagged enzyme in Escherichia coli BL21 (DE3)
dapB gene, overexpression from plasmid in Escherichia coli
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dapB gene, sequence determination, expression in Escherichia coli from plasmids
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expressed in Escherichia coli (BL21)
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expression of pET11a expression construct in Escherichia coli (BL21)
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
agriculture
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potential herbicide target, leads for herbicide development are inhibitors: dipicolinic acid, isophthalic acid, and DELTA3-tetrahydroisophthalic acid
drug development
-
enzyme is a potential target for new antimicrobial and herbicidal compounds
medicine
-
design and evaluation of dihydropicolinate reductase inhibitors as broad spectrum antibiotics and herbicides
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bouvier, J.; Richaud, C.; Richaud, F.; Patte, J.C.; Stragier, P.
Nucleotide sequence and expression of the Escherichia coli dapB gene
J. Biol. Chem.
259
14829-14834
1984
Escherichia coli
Manually annotated by BRENDA team
Tamir, H.; Gilvarg, C.
Dihydrodipicolinic acid reductase
J. Biol. Chem.
249
3034-3040
1974
Escherichia coli
Manually annotated by BRENDA team
Tamir, H.
Dihydrodipicolinic acid reductase (Escherichia coli)
Methods Enzymol.
17B
134-139
1971
Escherichia coli
-
Manually annotated by BRENDA team
Farkas, W.; Gilvarg, C.
The reduction step in diaminopimelic acid biosynthesis
J. Biol. Chem.
240
4717-4722
1965
Escherichia coli
Manually annotated by BRENDA team
Coulter, C.V.; Gerrard, J.A.; Kraunsoe, J.A.E.; Pratt, A.J.
Escherichia coli dihydrodipicolinate synthase and dihydrodipicolinate reductase: kinetic and inhibition studies of two putative herbicide targets
Pestic. Sci.
55
887-895
1999
Escherichia coli
-
Manually annotated by BRENDA team
Reddy, S.G.; Scapin, G.; Blanchard, J.S.
Interaction of pyridine nucleotide substrates with Escherichia coli dihydrodipicolinate reductase: Thermodynamic and structural analysis of binary complexes
Biochemistry
35
13294-13302
1996
Escherichia coli (P04036), Escherichia coli
Manually annotated by BRENDA team
Paiva, A.M.; Vanderwall, D.E.; Blanchard, J.S.; Kozarich, J.W.; Williamson, J.M.; Kelly, T.M.
Inhibitors of dihydrodipicolinate reductase, a key enzyme of the diaminopimelate pathway of Mycobacterium tuberculosis
Biochim. Biophys. Acta
1545
67-77
2001
Mycobacterium tuberculosis, Escherichia coli (P04036)
Manually annotated by BRENDA team
Reddy, S.G.; Sacchettini, J.C.; Blanchard, J.S.
Expression, purification, and characterization of Escherichia coli dihydrodipicolinate reductase
Biochemistry
34
3492-3501
1995
Escherichia coli
Manually annotated by BRENDA team
Scapin, G.; Reddy, S.G.; Zheng, R.; Blanchard, J.S.
Three-dimensional structure of Escherichia coli dihydrodipicolinate reductase in complex with NADH and the inhibitor 2,6-pyridinedicarboxylate
Biochemistry
36
15081-15088
1997
Escherichia coli (P04036), Escherichia coli
Manually annotated by BRENDA team
Scapin, G.; Blanchard, J.S.; Sacchettini, J.C.
Three-dimensional structure of Escherichia coli dihydrodipicolinate reductase
Biochemistry
34
3502-3512
1995
Escherichia coli
Manually annotated by BRENDA team
Ge, X.; Olson, A.; Cai, S.; Sem, D.S.
Binding synergy and cooperativity in dihydrodipicolinate reductase: implications for mechanism and the design of biligand inhibitors
Biochemistry
47
9966-9980
2008
Escherichia coli
Manually annotated by BRENDA team
Devenish, S.R.; Blunt, J.W.; Gerrard, J.A.
NMR studies uncover alternate substrates for dihydrodipicolinate synthase and suggest that dihydrodipicolinate reductase is also a dehydratase
J. Med. Chem.
53
4808-4812
2010
Escherichia coli
Manually annotated by BRENDA team
Trigoso, Y.D.; Evans, R.C.; Karsten, W.E.; Chooback, L.
Cloning, expression, and purification of histidine-tagged Escherichia coli dihydrodipicolinate reductase
PLoS ONE
11
e0146525
2016
Escherichia coli (P04036), Escherichia coli
Manually annotated by BRENDA team