Information on EC 1.14.13.9 - kynurenine 3-monooxygenase

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

EC NUMBER
COMMENTARY hide
1.14.13.9
-
RECOMMENDED NAME
GeneOntology No.
kynurenine 3-monooxygenase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
3-hydroxy-4-methyl-anthranilate biosynthesis I
-
-
3-hydroxy-4-methyl-anthranilate biosynthesis II
-
-
L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde
-
-
L-tryptophan degradation XI (mammalian, via kynurenine)
-
-
Metabolic pathways
-
-
tryptophan metabolism
-
-
Tryptophan metabolism
-
-
SYSTEMATIC NAME
IUBMB Comments
L-kynurenine,NADPH:oxygen oxidoreductase (3-hydroxylating)
A flavoprotein (FAD).
CAS REGISTRY NUMBER
COMMENTARY hide
9029-61-2
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
yellow fever mosquito, black-eyed Liverpool strain
SwissProt
Manually annotated by BRENDA team
Aedes aegypti Liverpool
yellow fever mosquito, black-eyed Liverpool strain
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
strain C108
-
-
Manually annotated by BRENDA team
strain C108
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
gene Tccn
SwissProt
Manually annotated by BRENDA team
wild-type and 3 mutants
-
-
Manually annotated by BRENDA team
ovariectomized female cynomolgus monkeys
-
-
Manually annotated by BRENDA team
male rhesus macaques
-
-
Manually annotated by BRENDA team
strain 17400
-
-
Manually annotated by BRENDA team
Rattus norvegicus Osborne-Mendel
Osborne-Mendel strain
-
-
Manually annotated by BRENDA team
red flour beetle
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
-
T helper 17 cells preferentially express kynurenine 3-monooxygenase. Enzyme inhibition, either with a specific inhibitor or via siRNA-mediated silencing, markedly increases IL-17 productionin vitro, whereas IFN-gamma production by T helper 1 cells is unaffected. Inhibition of kynurenine 3-monooxygenase significantly exacerbates disease in a Th17-driven model of autoimmune gastritis
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
kynurenine + NADPH + O2
3-hydroxy-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADH + H+ + O2
3-hydroxy-L-kynurenine + NAD+ + H2O
show the reaction diagram
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADPH + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADPH + O2
? + NADP+
show the reaction diagram
o-hydroxybenzoyl-DL-alanine + NADPH + O2
? + NADP+
show the reaction diagram
additional information
?
-
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
kynurenine + NADPH + O2
3-hydroxy-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADH + H+ + O2
3-hydroxy-L-kynurenine + NAD+ + H2O
show the reaction diagram
Q9MZS9
-
-
-
?
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADPH + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
show the reaction diagram
L-kynurenine + NADPH + O2
? + NADP+
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Br-
-
strong stimulation
Cl-
-
strong stimulation at 0.02 M
CN-
-
stimulates
F-
-
stimulates
I-
-
stimulates
NaCl
-
stabilizes
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(1S,2S)-2-(3,4-dichlorobenzoyl)-cyclopropane-1-carboxylic acid
-
KMO inhibitor UPF 648, totally blocks KMO at 0.1 and 0.01 mM and is still highly active at 0.001 mM (81% inhibition). It reduces 3-hydroxykynurenine synthesis by 64% without affecting kynurenic acid formation. In neuron-depleted striata, UPF 648 decreases both 3-hydroxykynurenine and quinolinic acid production by 77% and 66%, respectively and also raises kynurenic acid synthesis by 27%. 0.1 mM UPF 648 blocks KMO in both lesioned and contralateral striatum, but does not interfere with KAT activity in either tissue
(m-nitrobenzoyl)-alanine
(R,S)-2-amino-oxo-4-(3',4'-dichlorophenyl)butanoic acid
-
FCE 28833, 50% inhibition at 0.2 microM, blocks not only the cerebral but also the peripheral enzyme
(R,S)-2-amino-oxo-4-(3'-4'-dichlorophenyl)butanoic acid
-
-
(S)-9-(4-aminopiperazine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3,5,6-tetrahydro-4H-1-oxa-3a-azaphenalene-5-carboxylic acid
-
does not affect KMO activity significantly, 1 mM inhibits by 17%
2-benzyl-4-(3,4-dichlorophenyl)-4-oxo-butanoic acid
-
-
2-hydroxy-4-(3,4-dichlorophenyl)-4-oxobutanoic acid
-
-
2-oxo acid derivatives
-
of the 3 branched chain amino acids
2-oxoglutarate
-
mixed type inhibitor
3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide
3-nitrobenzoylalanine
-
-
4-(3,4-dichlorophenyl)-4-oxobutanoic acid
-
desamino FCE 28833
4-amino-N-[4-[2-fluoro-5-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
-
50% inhibition at 19nM
7-chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid
-
relatively potent and selective inhibitor
alpha-Ketoisocaproate
-
non competitive inhibition
anthranilic acid
-
22% inhibition at 2 mM and 11% inhibition at 0.2 mM
benzoylalanine
-
KMO inhibitor that mimics the substrate structure, and also stimulates reduction of the flavin by NADPH
chloride
mixed-type inhibition
Cl-
-
70% inhibition with 0.1 M NaCl or KCl, competitive with respect to NADPH and non-competitive with respect to L-kynurenine
EDTA
-
68% inhibition at 2 mM
KCl
-
high concentration
Kynurenic acid
-
13% inhibition at 2 mM and 5% inhibition at 0.2 mM
L-tryptophan
-
35% inhibition at 2 mM and 22% inhibition at 0.2 mM
m-nitrobenzoylalanine
-
KMO inhibitor that mimics the substrate structure, and also stimulates reduction of the flavin by NADPH
NADH
-
above 3 mM
p-chloromercuribenzoate
-
weak, 50% inhibition at 0.4 M
pyridoxal
-
less potent than pyridoxal phosphate
pyridoxal 5'-phosphate
pyruvate
-
mixed type inhibitor
Ro 61-8048
UPF 648
Xanthommatin
-
-
xanthurenic acid
-
48% inhibition at 2 mM and 13% inhibition at 0.2 mM
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
azide
-
0.005 M
Thiocyanate
-
0.01 M
additional information
-
a systemic inflammatory challenge stimulates KMO expression in brain, increased enzyme expression is observed in rat brain 24 h post lipopolysaccharide treatment, without any change in kynurenine aminotransferase II expression
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00012 - 0.0003
FAD
0.012 - 0.33
kynurenine
0.0164 - 0.89
L-kynurenine
5.17
NADH
recombinant enzyme, pH 7.5, 37C
0.0085 - 0.82
NADPH
0.034 - 0.071
O2
additional information
additional information
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.3 - 4.9
kynurenine
1.88
L-kynurenine
Aedes aegypti
Q86PM2
recombinant enzyme, pH 7.5, 37C
0.85
NADH
Aedes aegypti
Q86PM2
recombinant enzyme, pH 7.5, 37C
2.03
NADPH
Aedes aegypti
Q86PM2
recombinant enzyme, pH 7.5, 37C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000095
(R,S)-2-amino-oxo-4-(3'-4'-dichlorophenyl)butanoic acid
-
competitive inhibitor
0.0000048
3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide
-
competitive inhibitor
4.2 - 8.3
alpha-Ketoisocaproate
11.2 - 24.5
chloride
1
pyridoxal
-
-
0.17 - 0.27
pyridoxal 5'-phosphate
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000025
4-(3,4-dichlorophenyl)-4-oxobutanoic acid
Homo sapiens
-
pH 7.4, 25C
0.000035
Ro 61-8048
Homo sapiens
-
pH 7.4, 25C
0.0000003 - 0.000074
UPF 648
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.000012
-
liver of 2-3 months-old rats
0.0004
-
activity in kidney
0.0005
-
kidney
0.0015
-
activity in liver and in kidney
0.0022
-
liver
0.0025
0.004
-
kidney
0.028
-
NADPH oxidase activity
0.095
recombinant enzyme in crude Sf9 cell lysate
0.866
purified recombinant enzyme
2
-
fusion protein with glutathione-S-transferase
3.15
-
purified recombinant enzyme
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 9
-
about 50% of maximal activity at pH 7 and 9
7 - 9.3
-
about 50% of maximal activity at pH 7 and 9.3
7.1 - 8.9
-
about 50% of maximal activity at pH 7.1 and 8.9
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23
-
assay at
30
-
assay at
37
assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 10
-
50% activity at 7C and 10C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
villous, endothel
Manually annotated by BRENDA team
-
vascular, of villous blood vessels
Manually annotated by BRENDA team
-
placental
Manually annotated by BRENDA team
-
in first and second trimester of the placenta, within the fetal villus
Manually annotated by BRENDA team
-
especially in stromal and glandular epithelium in the first trimester decidua
Manually annotated by BRENDA team
-
in first and second trimester of the placenta
Manually annotated by BRENDA team
-
in first and second trimester of the placenta
Manually annotated by BRENDA team
-
T helper 17 cells preferentially express kynurenine 3-monooxygenase. Enzyme inhibition, either with a specific inhibitor or via siRNA-mediated silencing, markedly increases IL-17 productionin vitro, whereas IFN-gamma production by T helper 1 cells is unaffected. Inhibition of kynurenine 3-monooxygenase significantly exacerbates disease in a Th17-driven model of autoimmune gastritis
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
49000
-
SDS-PAGE
55000
-
SDS-PAGE
200000
-
or more, gel filtration, SDS-PAGE
345000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
2 * 160000 in 0.2% Triton-X100, SDS-PAGE
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structure, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active site structure, preventing productive binding of the substrate kynurenine
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 7
-
purified recombinant enzyme, 4C, stable
676975
8
-
purified recombinant enzyme, 4C, 10 h, loss of 21% of activity
676975
9
-
purified recombinant enzyme, 4C, 10 h, loss of 32% of activity
676975
10
-
purified recombinant enzyme, 4C, 3 h, complete inactivation
676975
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4
-
no loss of enzymatic activity after 24 hours
25
-
22% loss of enzymatic activity after 24 hours
37
-
stable for four hours
100
-
no enzymatic activity after boiling
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
disulfide reductants like dithiothreitol or 2-mercaptoethanol stabilize the enzyme
-
enzyme is protected against inactivation in the solubilized state by the presence of DTT, Triton X-100, and FAD in 0.1 M Tris-acetate buffer at pH 8.1
-
purified recombinant enzyme is highly unstable, activity decreases directly after purification also at -80C
solubilized enzyme is appreciably stabilized in 0.05 M Tris-acetate buffer, pH 8.1, 1 mM DTT, 0.2 M mannitol, 0.2% Triton X-100, 0.005 mM FAD
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70C no loss of enzymatic activity after 24 hours
-
-80C stable for 6 months
-
-80C, purified recombinant enzyme, not stable
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity chromatography
-
fusion protein with gluthatione-S-transferase
-
partial
recombinant enzyme 8.8fold from Escherichia coli strain by ammonium sulfate fractionation and ion exchange chromatography to homogeneity
-
recombinant enzyme from Sf9 insect cells by solubilization with Triton X-100 and affinity chromatography
recombinant His-tagged enzyme from soluble fraction of Sf9 insect cells by nickel affinity chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
AsK3H, DNA and amino acid sequence determination and analysis, functional expression in Spodoptera frugiperda Sf9 cells via the baculovirus infection system, membrane associated
DNA and amino acid sequence determnination and analysis, sequence comparisons, expression of FLAG-tagged wild-type enzyme and of C-terminal truncation mutants in COS-7 cells. The FLAG tag directs the wild-type enzyme to mitochondria but also to the cytosol and the plasma mambrane, overview
expression in baculoviral system
functional expression in Escherichia coli strain BL21 (DE3)
-
fusion protein with glutathione-S-transferase
-
gene kh, DNA and amino acid sequence analysis of wild-type and mutant genes, expression in Spodoptera frugiperda Sf9 cells as His-tagged, soluble protein via the baculovirus infection system
gene Tccn, homology-based cloning, DNA and amino acid sequence determination and analysis, gene structure analysis, the Tccn gene is located on linkage group 2
kinetic properties similar to the native liver enzyme
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
comprehensive panel of biochemical and cell-based assays that use liquid chromatography/tandem mass spectrometry to quantify unlabeled kynurenine and 3-hydroxykynurenine and application to measure kynurenine monooxygenase inhibition in cell and tissue extracts, as well as cellular assays
medicine
molecular biology
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