Information on EC 1.13.11.6 - 3-hydroxyanthranilate 3,4-dioxygenase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
1.13.11.6
-
RECOMMENDED NAME
GeneOntology No.
3-hydroxyanthranilate 3,4-dioxygenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
3-hydroxyanthranilate + O2 = 2-amino-3-carboxymuconate semialdehyde
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
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redox reaction
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-
-
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reduction
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
2-nitrobenzoate degradation I
-
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L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde
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L-tryptophan degradation XI (mammalian, via kynurenine)
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L-tryptophan degradation XII (Geobacillus)
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Metabolic pathways
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tryptophan metabolism
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Tryptophan metabolism
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SYSTEMATIC NAME
IUBMB Comments
3-hydroxyanthranilate:oxygen 3,4-oxidoreductase (decyclizing)
Requires Fe2+.
CAS REGISTRY NUMBER
COMMENTARY hide
9029-50-9
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
Hartley
-
-
Manually annotated by BRENDA team
Hartley
-
-
Manually annotated by BRENDA team
recombinantly expressed in Escherichia coli
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-
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
rainbow trout
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-
Manually annotated by BRENDA team
baboon
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-
Manually annotated by BRENDA team
strain KU-7
SwissProt
Manually annotated by BRENDA team
strain KU-7
SwissProt
Manually annotated by BRENDA team
Wistar strain
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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HAD belongs to the class of nonheme iron(II) enzymes and shares functional similarity with extradiol-cleaving catechol dioxygenases
physiological function
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the enzyme catalyzes the degradation of 3-hydroxyanthranilate to quinolinate in the presence of dioxygen
additional information
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oxidative CC bond cleavage of 2-amino-4-tert-butylphenolate on complex nonheme iron(II) complex, [(6-Me3-TPA)FeII(4-tBu-HAP)](ClO4) is mimicking the enzyme function. The iron(II)-aminophenolate complex reacts with molecular oxygen in acetonitrile under ambient conditions, overview
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-amino-3-hydroxybenzoic acid + O2
2,3-pyridinedicarboxylic acid + H2O
show the reaction diagram
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intermediate 2-amino-3-carboxymuconic acid semialdehyde
-
?
3-hydroxy-4-methylanthranilic acid + O2
?
show the reaction diagram
-
-
-
-
?
3-hydroxyanthranilate + O2
2-amino-3-carboxymuconate semialdehyde
show the reaction diagram
4-ethyl-3-hydroxyanthranilate + O2
2-amino-3-carboxy-4-ethylmuconate semialdehyde
show the reaction diagram
-
-
-
?
4-methyl-3-hydroxyanthranilate + O2
2-amino-3-carboxy-4-methylmuconate semialdehyde
show the reaction diagram
-
-
-
?
4-propyl-3-hydroxyanthranilic acid + O2
2-amino-3-carboxy-4-propylmuconate semialdehyde
show the reaction diagram
-
-
-
?
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-amino-3-hydroxybenzoic acid + O2
2,3-pyridinedicarboxylic acid + H2O
show the reaction diagram
Q0VCA8
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intermediate 2-amino-3-carboxymuconic acid semialdehyde
-
?
3-hydroxyanthranilate + O2
2-amino-3-carboxymuconate semialdehyde
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
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non-heme enzyme
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
(NH4)2SO4
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the most effective salt, the optimal concentration is 0.035 M
Fe
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each monomer contains two iron binding sites. The catalytic iron is buried deep inside the beta-barrel with His51, Glu57, and His95 serving as ligands. The other iron site forms an FeS4 center close to the solvent surface in which the sulfur atoms are provided by Cys125, Cys128, Cys162, and Cys165. The two iron sites are separated by 24 A
Fe3+
-
does not seem to bind to the enzyme
HCl
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during purification of enzyme treatment with acid was used
MgCl2
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NaCl
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Ni2+
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two nickel binding sites per molecule. One of the bound nickel atoms occupies the proposed ferrous-coordinated active site
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
Fe2+ chelator, 1 mM, complete inhibition
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide methiodide
carboxyl-directed reagent, 1 mM, 26% inhibition
2,2'-dipyridyl
Fe2+ chelator, 1 mM, complete inhibition
4,6-dibromo-3-hydroxyanthranilic acid
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NCR-631, characterization of in vivo effects, reversible inhibition with short half-life following systematic administration
4-Bromo-3-hydroxyanthranilic acid
4-Chloro-3-hydroxyanthranilate
4-Chloro-3-hydroxyanthranilic acid
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competitive
4-Fluoro-3-hydroxyanthranilic acid
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competitive
6-chloro-3-hydroxyanthranilic acid
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5-20 mM, loss of enzymatic activity as a function of the inhibitor concentration
acetaminophen
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Acetylsalicylic acid
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-
anthranilic acid
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competitive inhibition
Co2+
1 mM, 92% inhibition
Cu2+
0.1 mM, complete inhibition
diethyl dicarbonate
modifies histidine residues of catechol dioxygenases, 1 mM, 70% inhibition
Dithionitrobenzoic acid
cysteine-directed reagent, 1 mM, complete inhibition
EDTA
1 mM, 99% inhibition
Fe3+
0.1 mM, 82% inhibition
iodoacetate
cysteine-directed reagent, 1 mM, 42% inhibition
Ni2+
1 mM, 82% inhibition
o-methoxybenzoylalanine
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in whole-liver homogenates, but in purified enzyme preparations only in the presence of mitochondria
p-chloromercuribenzoate
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p-Chloromercuriphenyl sulfonic acid
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quinolinic acid
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competitive inhibition
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Triton X-100
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
36 - 57
3-hydroxy-4-methylanthranilic acid
-
-
0.0102 - 19
3-Hydroxyanthranilate
0.002 - 0.105
3-hydroxyanthranilic acid
0.011
4-ethyl-3-hydroxyanthranilic acid
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-
0.037
4-methyl-3-hydroxyanthranilic acid
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-
0.01
4-Propyl-3-hydroxyanthranilic acid
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-
0.615
O2
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-
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0046 - 25
3-Hydroxyanthranilate
additional information
additional information
Homo sapiens
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-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00004
4-Bromo-3-hydroxyanthranilic acid
-
competitive
0.00003
4-Chloro-3-hydroxyanthranilic acid
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competitive
0.00019
4-Fluoro-3-hydroxyanthranilic acid
-
competitive
12
6-chloro-3-hydroxyanthranilic acid
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-
2 - 6.5
anthranilic acid
1.8
quinolinic acid
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for the pI 5.6 enzyme
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0003
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brain
0.0075
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liver
7.9
3-hydroxyanthranilate as substrate, pH 6.5, 30C
115.7
-
last purification step
140
-
-
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.9 - 7.4
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7.4 - 7.6
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additional information
-
pI: 5.2
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.5 - 7
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at pH 4.5: about 70% of activity maximum, at pH 7.0: about 50% of activity maximum
5 - 7.5
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determination on heat-reactivated extracts after inactivation
additional information
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at pH 3.4: the enzyme is in a form which can bind substrate but is enzymatically inactive, at pH 6.5: active form of enzyme
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
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assay at
37
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assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0 - 50
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enzyme activity increased almost linearly with temperature, beyond a sharp drop
55
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activation by heating at 55C for 5 min
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4.98
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chromatofocusing in PBE 94 gel exchanger and polybuffer 74, pH 4-7.4
5.6
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chromatofocusing in PBE 94 gel exchanger and polybuffer 74, pH 4-7.4
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Cupriavidus metallidurans (strain ATCC 43123 / DSM 2839 / NBRC 102507 / CH34)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21240
predicted from cDNA sequence
32520
-
PAGE in nondenaturing conditions, pI 4.98 enzyme
32570
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PAGE in nondenaturing conditions, pI 5.6 enzyme
32590
-
ion spray MS, recombinant enzyme
32600
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immunoblot analysis, recombinant enzyme
32630
-
ion spray MS
33000 - 34000
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gel filtration
34000
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gel filtration, readily aggregates to form inactive higher molecular weight oligomers
35000 - 40000
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gel filtration, SDS-PAGE
36000
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SDS-PAGE
37000 - 38000
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gel filtration, SDS-PAGE, sucrose density gradient centrifugation
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
first vapor diffusion with sitting drop method starting from protein concentration of 10 mg/ml in 32% (NH4)2SO4, 0.1 M sodium acetate, 10 mM 2-mercaptoethanol, pH 5, subsequently, crystals can be obtained by seeding starting from fragments of first crystallization experiments using 40% (NH4)2SO4, Tris-HCl, 40 mM MgCl2, 3% MPD, pH 8 as precipitant
hanging drop method
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hanging drop-vapor diffusion method, 2.4 A resolution
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5
-
most stable, above extremly unstable
439369
10
-
4C, half-life: 3 days
439364
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0 - 4
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stable for a month, in Tris-maleate buffer, pH 6.5
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
stability of enzyme in crude extract
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thawing and refreezing: crude enzyme extract at 20C, relatively stable in presence of Fe2+, about 30% loss of activity after 2 thawings
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ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-15C, in 0.01 M Tris buffer, pH 7.0, 4 days, no loss of activity
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-80C, as homogenate stable for 2 months
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-90C, frozen in dry ice-ethanol bath, partially purified enzyme is stable for at least 1 month, purified enzyme is unstable
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0C, 0.01 M collidine chloride, 0.01 M potassium chloride, pH 6.5, about 15% loss of activity after 1 month, purified enzyme
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0C, 66.7 mM Tris-HCl buffer, pH 8.0, 90 min, approximately 25% loss of activity
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25C, 66.7 mM Tris-HCl buffer, pH 8.0, 90 min, approximately 70% loss of activity
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4C, overnight, 75% loss of activity
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4C, overnight, about 75% loss of activity
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
bovine kidney homogenized in 0.1 M potassium dihydrogen phosphate buffer with 20% glycerol and 3 mM 2-mercaptoethanol, pH 7.4, centrifuged, protein fraction of supernatant that precipitates from 34-62% saturated (NH4)2SO4 is resuspended in 5 mM potassium dihydrogen phosphate buffer with 20% glycerol and 3 mM 2-mercaptoethanol, pH 7.4, dialyzed against same buffer containing protease inhibitor PMSF (0.1 mM), applied to DEAE Sephadex A-50 column, fractions with enzyme activity pooled and concentrated by precipitation with 80%-saturated (NH4)2SO4, dialyzed against 10 mM Tris-HCl with 20% glycerol and 3 mM 2-mercaptoethanol, pH 7.4, applied to Blue-Sepharose CL-4B column, concentration of active fractions by ultrafiltration through YM-10 membrane
pure liver enzyme, partielly purified brain enzyme
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succesive size exclusion and affinity columns
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
expression in human embryonic kidney HEK-293
-
Y3HAO protein is subcloned into the pET-28a expression vector from extracted Saccharomyces cerevisiae genomic DNA, and the Y3HAO protein is highly expressed as a soluble protein in Escherichia coli strain BL21(DE3) with a six-residueHis tag attached to its N-terminus
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E110A
-
kcat/Km is 954fold lower than wild-type enzyme
R47A
-
kcat/Km is 7440fold lower than wild-type enzyme. Mutant enzyme shows substrate inhibition
R99A
-
kcat/Km is 22320fold lower than wild-type enzyme
H52A
inactive enzyme
H93A
24.8% activity of the native enzyme
H96A
inactive enzyme
H52A
-
inactive enzyme
-
H93A
-
24.8% activity of the native enzyme
-
H96A
-
inactive enzyme
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
-
plays a role in disorders, associated with altered tissue levels of quinolinic acid
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