Information on EC 4.1.3.16 - 4-Hydroxy-2-oxoglutarate aldolase

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The expected taxonomic range for this enzyme is: Mammalia

EC NUMBER
COMMENTARY hide
4.1.3.16
-
RECOMMENDED NAME
GeneOntology No.
4-Hydroxy-2-oxoglutarate aldolase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
4-hydroxy-2-oxoglutarate = pyruvate + glyoxylate
show the reaction diagram
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
condensation
-
-
-
-
elimination
-
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of an oxo-acid, C-C bond cleavage
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Arginine and proline metabolism
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Glyoxylate and dicarboxylate metabolism
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Metabolic pathways
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trans-4-hydroxy-L-proline degradation I
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SYSTEMATIC NAME
IUBMB Comments
4-hydroxy-2-oxoglutarate glyoxylate-lyase (pyruvate-forming)
The enzymes from rat liver and bovine liver act on both enantiomers of 4-hydroxy-2-oxoglutarate. cf. EC 4.1.3.42, L-4-hydroxy-2-oxoglutarate aldolase.
CAS REGISTRY NUMBER
COMMENTARY hide
9030-81-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-Keto-4-hydroxybutyrate
?
show the reaction diagram
-
metabolism of L-homoserine
-
-
-
2-Keto-4-hydroxybutyrate
Pyruvate + formaldehyde
show the reaction diagram
-
D-isomer favoured
-
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4-hydroxy-2-oxoglutarate
?
show the reaction diagram
4-Hydroxy-2-oxoglutarate
Pyruvate + glyoxylate
show the reaction diagram
D-4-hydroxy-2-oxoglutarate
pyruvate + glyoxylate
show the reaction diagram
-
-
-
-
r
Glyoxylate + pyruvate
4-Hydroxy-2-ketoglutarate
show the reaction diagram
L-4-hydroxy-2-oxoglutarate
pyruvate + glyoxylate
show the reaction diagram
-
-
-
-
r
Oxaloacetate
CO2 + pyruvate
show the reaction diagram
Pyruvate + formaldehyde
2-Keto-4-hydroxybutyrate
show the reaction diagram
-
Keq: 4.1 mM
-
-
pyruvate + glyoxylate
D-4-hydroxy-2-oxoglutarate
show the reaction diagram
-
-
-
-
r
additional information
?
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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
2-Keto-4-hydroxybutyrate
?
show the reaction diagram
-
metabolism of L-homoserine
-
-
-
4-hydroxy-2-oxoglutarate
?
show the reaction diagram
4-Hydroxy-2-oxoglutarate
Pyruvate + glyoxylate
show the reaction diagram
-
-
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-Ketobutyrate
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competitive, Ki for 2-keto-4-hydroxybutyrate cleavage: 53 mM, Ki for 2-keto-4-hydroxyglutarate cleavage: 52 mM
2-Ketoglutarate
4-hydroxy-2-oxoglutarate
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substrate inhibition, Ki: 35 mM
5,5'-dithiobis(2-nitrobenzoate)
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glyoxylate and pyruvate protect
acetaldehyde
-
-
arsenite
-
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beta-Hydroxypyruvate
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-
Bromopyruvate
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Ki: 0.018 mM
chloride
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41% inhibition at 40 mM
citrate
-
-
CN-
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irreversible, in presence of aldehydes, reversible in abscence of aldehydes, 2-keto-4-hydroxyglutarate cleavage, Ki: 0.57 mM
Cu2+
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93% inhibition at 2 mM
cysteine
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65% inhibition at 10 mM
Dithiodipyridine
-
kidney enzyme
glycolaldehyde
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competitive, Ki for 2-keto-4-hydroxybutyrate cleavage: 2.7 mM, Ki for 2-keto-4-hydroxyglutarate cleavage: 2.4 mM
Glyoxal
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36% inhibition at 20 mM
glyoxylate
Halides
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-
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Hydroxypyruvate
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91% inhibition at 20 mM
iodoacetate
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10% inhibition at 10 mM
Mercaptopyruvate
-
-
Mn2+
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65% inhibition at 10 mM; kidney enzyme, 65% inhibition at 10 mM
N-ethylmaleimide
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64% inhibition at 10 mM
NaCl
-
-
NaI
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-
oxaloacetate
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competitive, Ki: 0.22 mM
p-chloromercuribenzoate
p-mercuribenzoate
-
kidney enzyme
pyruvate
Sulfhydryl-reacting reagents
-
-
-
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-mercaptoethanol
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50 mM, enhances activity 2fold; activates kidney enzyme
KCl
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activates
additional information
-
carboxylic acids activate
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.11 - 0.14
(D)-4-hydroxy-alpha-ketoglutarate
0.22 - 71
(L)-4-hydroxy-alpha-ketoglutarate
3.1
2-Keto-4-hydroxybutyrate
-
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7.7
3-(4-hydroxyphenyl)pyruvate
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7.4
3-(4-imidazole)pyruvate
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-
0.008 - 0.281
4-hydroxy-2-oxoglutarate
0.1 - 1.33
4-hydroxy-alpha-ketoglutarate
10
acetaldehyde
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0.031
D-4-hydroxy-2-oxoglutarate
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pH 8.3, 37C
0.43
glyoxylate
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0.024
L-4-hydroxy-2-oxoglutarate
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pH 8.3, 37C
30
oxaloacetate
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condensation with glyoxylate
5.1
Pyruvaldehyde
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10 - 25
pyruvate
2.8
Pyruvic acid ethyl ester
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3.2
pyruvic acid methyl ester
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-
additional information
additional information
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.8 - 7.8
4-hydroxy-2-oxoglutarate
13.5
DL-2-keto-4-hydroxyglutarate
Bos taurus
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
14 - 650
4-hydroxy-2-oxoglutarate
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
35
4-hydroxy-2-oxoglutarate
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substrate inhibition
0.018
Bromopyruvate
-
-
0.22
oxaloacetate
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competitive
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.53
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2-keto-4-hydroxybutyrate
1.8
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2-keto-4-hydroxyglutarate
9.23
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kidney enzyme; pH 8.4, 37C
9.7
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15.8
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pH 8.5, 37C
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 8
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condensation, elimination
8.1
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2-keto-4-hydroxybutyrate cleavage
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 9.5
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2-keto-4-hydroxybutyrate cleavage
6.3
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50% of maximum activity
7 - 9
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2-keto-4-hydroxyglutarate cleavage
9.6
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60% of maximum activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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poor activity
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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11% of total activity
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Bacillus cereus (strain ATCC 14579 / DSM 31 / JCM 2152 / NBRC 15305 / NCIMB 9373 / NRRL B-3711)
Vibrionales bacterium (strain SWAT-3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
72000
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gel filtration
97200
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sedimentation equilibrium centrifugation
120000
131500
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gel filtration
138000
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sucrose density gradient centrifugation
140000
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gel filtration
144000
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gel filtration, sucrose density gradient centrifugation, kidney enzyme
144500
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sedimentation equilibrium centrifugation
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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and tetramer, in equilibrium, 2 * 35249, calculated
tetramer
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
to 1.97 A resolution, crystal structure of enzyme bound to pyruvate. Modeling of the 4-hydroxy-2-oxoglutarate-Schiff base intermediate and kinetic analyses of site-directed mutants support the importance of Lys196 as the nucleophile, Tyr168 and Ser77 as components of a proton relay, and Asn78 and Ser198 as unique residues that facilitate substrate binding
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
59
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constant decay of 0.011 1/min, slow inactivation
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
irreversibly inactivated by aminonitrile formation from cyanide and enzyme-substrate complex
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4C, Tris-HCl buffer, pH 7.4, 40% saturated with ammonium sulfate, 6 months, kidney enzyme
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4C, in either 50 mM Tris-HCl or potassium phosphate, pH 7.4, plus 5 mM 2-mercaptoethanol, 0.02% sodium azide, 40% saturated with ammonium sulfate, 100% of initial activity for at least 6 months
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4C, in either 50 mM Tris-HCl or potassium phosphate, pH 7.4, plus 5 mM 2-mercaptoethanol, 0.02% sodium azide, no substantial loss of enzymatic activity for up to 1 month
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5C, Tris-HCl buffer, pH 7.4, two weeks, sometimes several months
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; kidney enzyme
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
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genotyping in 28 patients with type 3 atypical primary hyperoxaluria, overview
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C257G
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
DeltaE315
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
G287V
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
K196A
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complete loss of activity
N78A
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20% of wild-type activity
N78Q
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4% of wild-type activity
N78T
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45% of wild-type activity
P190L
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
R255X
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a truncation of 71 residues from the C-terminus associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
R303C
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
R70P
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
R97C
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
S198A
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9% of wild-type activity
S198T
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18% of wild-type activity
S77A
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5% of wild-type activity
S77T
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2% of wild-type activity
S77V
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2% of wild-type activity
T280I
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natural mutation associated with Primary Hyperoxaluria type 3. Mutant is quite unstable, has a tendency to aggregate, and retains no measurable activity
Y140F
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122% of wild-type activity
Y168F
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complete loss of activity
Y39X/R70X
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naturally occuring mutations in a patient with type 3 atypical primary hyperoxaluria
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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mutations in the gene encoding for 4-hydroxy-2-oxoglutarate aldolase are associated with an excessive production of oxalate in Primary Hyperoxaluria type 3, PH3. Analysis of nine PH3 human variants reveals that all nine PH3 variants are quite unstable, have a tendency to aggregate, and retain no measurable activity. A buildup of 4-hydroxy-2-oxoglutarate takes place in the urine, sera and liver samples from PH3 patients. One hypothetical component of the molecular basis for the excessive oxalate production in PH3 appears to be the inhibition of glyoxylate reductase by 4-hydroxy-2-oxoglutarate, resulting in a phenotype similar to Primary Hyperoxaluria type 2
synthesis
-
use as synthetic tool for C-C bond formation considered
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