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Information on EC 1.14.13.9 - kynurenine 3-monooxygenase and Organism(s) Pseudomonas fluorescens and UniProt Accession Q84HF5
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1.14.13.9 kynurenine 3-monooxygenaseIUBMB Comments
A flavoprotein (FAD).
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Word Map
- 1.14.13.9
- mercury
- hg
-
kynurenic
- 3-hydroxykynurenine
-
quinolinic
-
2,3-dioxygenase
- kynureninase
- indoleamine
-
cronbach
- huntington
-
bartlett
-
paint
-
3-hydroxyanthranilic
-
quin
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neuroactive
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ochre
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psychometric
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calcite
- methylmercury
-
xanthurenic
-
eigenvalue
-
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-
hematite
-
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-
excitotoxins
-
ommochrome
-
artwork
-
geochemical
- indoleamine-2,3-dioxygenase
-
archaeological
-
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-
roman
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mineralogical
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slovenia
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micro-raman
- molecular biology
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- pharmacology
The taxonomic range for the selected organisms is: Pseudomonas fluorescens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
cinnabar, kmo, kynurenine 3-monooxygenase, kynurenine 3-hydroxylase, kynurenine hydroxylase, kynurenine monooxygenase, kynurenine-3-monooxygenase, pfkmo, kyn-ohase, nadph-dependent flavin monooxygenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
flavin adenine dinucleotide dependent kynurenine 3-monooxygenase
-
kynurenine 3-hydroxylase
-
-
-
-
kynurenine hydroxylase
-
-
-
-
L-kynurenine-3-hydroxylase
-
-
-
-
oxygenase, kynurenine 3-mono-
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O
catalytic reaction mechanism, overview
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O
mechanism of kynurenine 3-monooxygenase-catalyzed hydroxylation reaction, quantum mechanical calculations on the hydroxylation reaction of the kynurenine pathway, which involves the oxidative half-reaction with low reaction rates, modeling by cluster method, detailed overview. The modeled mechanism involves four successive transformations: Somersault rearrangement (rate-determining step), hydride shift, keto-enol tautomerization, and the dehydration with facile barriers
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O
the mechanism of KMO is typical of class A FAH enzymes that exhibit ping-pong kinetics in which the aromatic substrate binds first, followed by NADPH and the reduction of FAD. The NADP+ formed must then dissociate prior to the addition of molecular oxygen and the commencement of the oxidative catalytic steps. The ping-pong mechanism thus facilitates the observation of the reductive and oxidative half-reactions in separate experiments by controlling the availability of the third substrate, dioxygen. The three phases observed during the oxidative half reaction are formation of the hydroperoxyflavin, hydroxylation and product release. Reaction via C4a-hydroperoxyflavin intermediate. The oxidative half-reaction is indeed the hydroxylation step and that the aromatic position C3 of L-Kyn experiences a sp2 to sp3 hybridization change for the transition state that occurs with electrophilic attack by the hydroperoxyflavin. A non-aromatic species is the immediate product of hydroxylation and that at least two solvent derived protons are in-flight during oxygen insertion to the substrate aromatic ring. A hydroxylation transition state in which two protons are shared between the proximal and distal oxygens of the C4a-hydroperoxide as the O-O bond is broken and as sp3 character is developed at the site of hydroxylation. Such a mechanism has the C4a-oxide and the diene-imine protonated simultaneously with the requisition of one these two protons from a water molecule. Proposed mechanisms of the oxidative half-reaction of KMO, detailed overview
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O
the mechanism of L-Kyn catalysis by KMO is composed of reductive and oxidative half reactions. The binding of the substrate induces the reduction of FAD by NADH or by NADPH
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
L-kynurenine,NADPH:oxygen oxidoreductase (3-hydroxylating)
A flavoprotein (FAD).
CAS REGISTRY NUMBER
COMMENTARY
9029-61-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-kynurenine + NADPH + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
-
binding of L-kynurenine to the oxidized enzyme is relatively slow and involves at least two reversible steps
-
-
?
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
-
-
-
?
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
-
-
-
-
?
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
-
-
-
?
kynurenine + NADPH + O2
3-hydroxy-kynurenine + NADP+ + H2O
-
the reaction is central to the tryptophan degradative pathway, overview, and takes place within microglial cells defining cellular concentrations of the N-methyl-D-aspatate receptor agonist quinolinate and antagonist kynurenate
the product acts as apoptotic signal
-
ir
kynurenine + NADPH + O2
3-hydroxy-kynurenine + NADP+ + H2O
-
enzyme activity depends on the reduction state of the enzyme
-
-
ir
additional information
?
-
density functional theory (DFT) calculations in the absence and in the presence of the kynurenine 3-monooxygenase (KMO) enzyme, crystal structure (PDB ID 5NAK)-based calculations involved a quantum cluster model in which the active site of the enzyme with the substrate L-Kyn is represented with 348 atoms. According to the deduced mechanism, KMO-catalyzed hydroxylation reaction takes place with four transformations. In the initial transition state, FAD delivers its peroxy hydroxyl to the L-Kyn ring, creating an sp3-hybridized carbon center. Then, the hydrogen on the hydroxyl moiety is immediately transferred back to the proximal oxygen that remains on FAD. These consequent transformations are in line with the somersault rearrangement previously described for similar enzymatic systems. The second step corresponds to a hydride shift from the sp3-hybridized carbon of the substrate ring to its adjacent carbon, producing the keto form of 3-HK. Then, keto-3-HK is transformed into its enol form (3-HK) with a water-assisted tautomerization. Lastly, FAD is oxidized with a water-assisted dehydration, which also involves 3-HK as a catalyst. Residues Asn54, Pro318, and a crystal water molecule are seen to play significant roles in the proton relays
-
-
-
additional information
?
-
the mechanism of L-Kyn catalysis by KMO is composed of reductive and oxidative half reactions. The binding of the substrate induces the reduction of FAD by NADH or by NADPH. The initiation of FAD reduction is not unique to the substrate binding. It is also observed upon the binding of several inhibitors. The molecules that induce reduction of FAD other than the substrate are named as non-substrate effectors, e.g. GSK180 and Ro 61-8048 for enzyme pfKMO. Since the non-substrate effectors eliminate the hydroxyl transfer event but nonetheless initiate the formation of the FAD-hydroperoxide intermediate, they cause hydrogen peroxide formation. The triggering factor can arise from the substrate induced conformational changes in the loop above the isoalloxazine ring system
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-kynurenine + NADPH + H+ + O2
3-hydroxy-L-kynurenine + NADP+ + H2O
-
-
-
?
kynurenine + NADPH + O2
3-hydroxy-kynurenine + NADP+ + H2O
-
the reaction is central to the tryptophan degradative pathway, overview, and takes place within microglial cells defining cellular concentrations of the N-methyl-D-aspatate receptor agonist quinolinate and antagonist kynurenate
the product acts as apoptotic signal
-
ir
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
KMO has an FAD cofactor, utilizes either NADPH or NADH, releases NADP+ /NAD+ after flavin reduction, and has one dinucleotide-binding domain. Rossmann fold simply characterizes a secondary structure with an alternating motif of beta sheets and alpha helices, and is of importance because this domain non-covalently binds the FAD cofactor and also contains the active site of the enzyme for KMO
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(R)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoate
-
(S)-3-(5-Chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoate
-
3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzene-1-sulfonamide
Ro 61-8048, different binding modes of the inhibitor Ro 61-8048 in scKMO and in pfKMO, overview
-
3-(5,6-dichloro-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-propanoic acid
-
3-(5-chloro-6-cyclopropoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
-
3-(5-chloro-6-ethoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
-
3-(5-chloro-6-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
-
3-(5-chloro-6-methoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-propanoic acid
-
3-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
-
3-[5-chloro-2-oxo-6-(pyridin-2-ylmethoxy)-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-2-oxo-6-[(1R)-1-(pyridazin-3-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-2-oxo-6-[(1R)-1-(pyridin-2-yl)ethoxy]-2,3-dihydro-1,3-benzothiazol-3-yl]propanoic acid
-
3-[5-chloro-2-oxo-6-[(1R)-1-(pyrimidin-2-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-2-oxo-6-[1-(pyridin-2-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-2-oxo-6-[2-(pyrrolidin-1-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-6-(2-methoxyethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-(cyclobutylmethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-(cyclopropylmethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-6-[(1R)-1-(1,3-oxazol-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(4-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-chloropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-chloropyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-methylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]-propanoic acid
-
3-[5-chloro-6-[(1R)-1-(5-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(6-methylpyridazin-3-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(6-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[5-chloro-6-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
-
3-[6-(benzyloxy)-5-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
-
3-[6-chloro-3-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl]propanoic acid
-
3-[6-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]-1H-indazol-1-yl]propanoic acid
-
3-[6-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]-1H-indol-1-yl]-propanoic acid
-
Cl-
low concentrations of NaCl solution stabilize the enzyme and decrease the limiting rate of reduction by 30fold. This effect is specific to the Cl- anion. The rate of hydroxylation is also moderately reduced with the introduction of NaCl solution
benzoylalanine
-
KMO inhibitor that mimics the substrate structure, and also stimulates reduction of the flavin by NADPH
m-nitrobenzoylalanine
-
KMO inhibitor that mimics the substrate structure, and also stimulates reduction of the flavin by NADPH
Ro 61-8048
noncompetitive. Theinhibitor is bound in the tunnel at the interface where the N- and C-terminal domains associate
additional information
development and optimization of a series of inhibitors
-
additional information
the molecular mechanism of action of three classes of inhibitors with differentiated binding modes and kinetics is reported. Two inhibitor classes trap the catalytic flavin in a tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production
-
additional information
enzyme structure and ligand interaction analysis using the crystal structure of pfKMO (PDB ID 5NAK), library screening from Zinc15 database, detailed overview
-
additional information
-
targeted inhibition of KMO is a viable strategy for achieving local elevation of kynurenate concentrations
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
evaluation of the proton inventory resulting from medium effects or specific transition states, first-order rate constants are fit to variations of the Kresge (Gross-Butler) equation, kinetic isotope effects, oxidative half-reaction in the presence of ring perdeutero-L-Kyn, stopped-flow spectrophotometric measurements, kinetics, overview. The decay of the C4a-hydroperoxyflavin results in the regeneration of the oxidized flavin. The final step of the oxidative half-reaction is then the release of 3-hydroxy-L-kynurenine from the active site which is observed as a perturbation of the oxidized absorption spectrum
-
additional information
additional information
-
evaluation of the proton inventory resulting from medium effects or specific transition states, first-order rate constants are fit to variations of the Kresge (Gross-Butler) equation, kinetic isotope effects, oxidative half-reaction in the presence of ring perdeutero-L-Kyn, stopped-flow spectrophotometric measurements, kinetics, overview. The decay of the C4a-hydroperoxyflavin results in the regeneration of the oxidized flavin. The final step of the oxidative half-reaction is then the release of 3-hydroxy-L-kynurenine from the active site which is observed as a perturbation of the oxidized absorption spectrum
-
additional information
additional information
-
steady-state kinetics and ligand perturbation of flavin fluorescence, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0135
Ro 61-8048
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000025
(R)-3-(5-chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoate
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00025
(S)-3-(5-Chloro-2-oxo-6-(1-(pyridin-2-yl)ethoxy)benzo[d]oxazol-3(2H)-yl)propanoate
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000063
3-(5,6-dichloro-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-(5-chloro-6-cyclopropoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-(5-chloro-6-ethoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00001
3-(5-chloro-6-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000013
3-(5-chloro-6-methoxy-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000126
3-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-2-oxo-6-(pyridin-2-ylmethoxy)-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000013
3-[5-chloro-2-oxo-6-[(1R)-1-(pyridazin-3-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000002
3-[5-chloro-2-oxo-6-[(1R)-1-(pyridin-2-yl)ethoxy]-2,3-dihydro-1,3-benzothiazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-[5-chloro-2-oxo-6-[(1R)-1-(pyrimidin-2-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-2-oxo-6-[1-(pyridin-2-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000794
3-[5-chloro-2-oxo-6-[2-(pyrrolidin-1-yl)ethoxy]-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000032
3-[5-chloro-6-(2-methoxyethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000013
3-[5-chloro-6-(2-methylpropyl)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000025
3-[5-chloro-6-(cyclobutylmethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00001
3-[5-chloro-6-(cyclopropylmethoxy)-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-6-[(1R)-1-(1,3-oxazol-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00000398
3-[5-chloro-6-[(1R)-1-(4-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-6-[(1R)-1-(5-chloropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00000316
3-[5-chloro-6-[(1R)-1-(5-chloropyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-6-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000025
3-[5-chloro-6-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000032
3-[5-chloro-6-[(1R)-1-(5-methylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00000316
3-[5-chloro-6-[(1R)-1-(5-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000002
3-[5-chloro-6-[(1R)-1-(6-methylpyridazin-3-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-[5-chloro-6-[(1R)-1-(6-methylpyridin-2-yl)ethoxy]-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-[5-chloro-6-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000025
3-[6-(benzyloxy)-5-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-[6-chloro-3-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.00000316
3-[6-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]-1H-indazol-1-yl]propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.000005
3-[6-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]-1H-indol-1-yl]-propanoic acid
Pseudomonas fluorescens
pH and temperature not specified in the publication
0.0000007
GSK366
Pseudomonas fluorescens
pH 7.5, temperature not specified in the publication
0.00006
GSK428
Pseudomonas fluorescens
pH 7.5, temperature not specified in the publication
0.000003
GSK775
Pseudomonas fluorescens
pH 7.5, temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
pH dependence of the oxidative half reaction of KMORED-mNBA complex, overview
additional information
-
pH dependence of the oxidative half reaction of KMORED-mNBA complex, overview
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
the enzyme is a clinical candidate for the treatment of acute pancreatitis
evolution
metabolism
physiological function
additional information
evolution
KMO belongs to a family of NAD(P)H-dependent flavin monooxygenase (FMO). KMO has one dicucleotide binding domain, which simply categorizes it as a Class A flavoprotein aromatic hydroxylase
evolution
KMO is a class A external flavoprotein aromatic hydroxylase (FAH). This class of enzymes uses the isoalloxazine ring of FAD to mediate the delivery of electrons from singlet state NADPH to the molecular oxygen ground state triplet in order to promote subsequent hydroxylation of singlet state molecules
metabolism
FAD-dependent kynurenine 3-monooxygenase (KMO) catalyzes the conversion of L-kynurenine (L-Kyn) to 3-Hydroxykynurenine (3-HK) in the kynurenine pathway. In the pathway responsible for the catabolism of tryptophan, enzyme KMO regulates the levels of bioactive substances. L-Kyn, is also a substrate to both kynureninase (KYNU) and especially to kynurenine aminotransferase (KAT), which converts L-Kyn to kynurenic acid (KynA); a neuroprotective agent for being the antagonist of NMDA, alpha-7 nicotinic acetylcholine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate, and an antioxidant for being the scavenger of several free radical species
metabolism
kynurenine 3-monoxygenase (KMO) catalyzes the conversion of L-kynurenine (L-Kyn) to 3-hydroxykynurenine (3-OHKyn) in the pathway for tryptophan catabolism. The KMO active site is insulated from exchange with solvent during catalysis
metabolism
the enzyme is involved in the kynurenine pathway (KP) that is the essential metabolic pathway for the catabolism of tryptophan. L-kynurenine (KYN) is the key and first stable intermediate of the KP by a formamidase. There are three possible metabolic fates for KYN, which involve biotransformations with (1) kynurenine aminotransferase (KAT) to form kynurenic acid (KynA), (2) kynureninase to form anthranilic acid, and (3) kynurenine 3-monooxygenase (KMO) to form 3-hydroxykynurnine (3-HK). 3-Hydroxykynurnine (3-HK) further leads to the formation of picolinic acid, 3-HANA, cinnabarinic acid, and quinolinic acid (QUIN). Three metabolites, QUIN, 3-HK, and 3-HANA, have been shown to be neurotoxic
physiological function
KMO is a flavin-dependent hydroxylase that catalyzes the hydroxylation of L-kynurenine (L-Kyn) to 3-hydroxykynurenine (3-HK) in the kynurenine pathway (KP). The kynurenine pathway (KP) is the major mechanism for tryptophan catabolism with up to 99% of tryptophan being metabolized this way
physiological function
kynurenine 3-monooxygenase (KMO) regulates the levels of bioactive substances in the kynurenine pathway of tryptophan catabolism and its activity is tied to many diseases. The product of the enzyme reaction, 3-hydroxy-L-kynurenine (3-HK), is a neurotoxic agent that induces apoptosis and damages wide range of cell types. It is further converted to the free-radical generator 3-hydroxyanthranilate (3-HanA) which is then converted to the selective N-methyl-D-aspartate (NMDA) receptor agonist quinolinate
additional information
a Rossmann fold simply characterizes a secondary structure with an alternating motif of beta sheets and alpha helices, and is of importance because this domain non-covalently binds the FAD cofactor and also contains the active site of the enzyme for KMO
additional information
PfKMO is active without its membrane targeting domain, structure comparisons with the enzymes from Saccharomyces cerevisiae and Homo sapiens, overview
additional information
the structure reveals that the aniline moiety of L-Kyn is stacked roughly perpendicular to the isoalloxazine of the FAD and that the C3 of the substrate is within 4.6 A of the flavin C4a position
additional information
-
the structure reveals that the aniline moiety of L-Kyn is stacked roughly perpendicular to the isoalloxazine of the FAD and that the C3 of the substrate is within 4.6 A of the flavin C4a position
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
the structure of KMO can be realized as three domains: the first domain is where FAD is buried within beta-sheets and alpha-helices, one of which is the long alpha-helix that leads to the C-terminal domain. This helix and a loop that stands above the isoalloxazine rings of FAD define the borders of the active site in this region. The second region contains the residues of alpha-helices and beta-sheets whose side chains set the final border to the active site. Therefore, the active site is contained at the interface of the first and second regions. The third region of PfKMO consists of four alpha-helices while in scKMO and hKMO there are only the two alpha-helices of the transmembrane domain
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystals are obtained by hanging-drop vapor diffusion at 20°C. Crystal structures of the complex of the full-length enzyme with the substrate L-kynurenine and in complex with L-kynurenine and Ro 61-8048 at a resolution of 1.85 and 2.34 A, respectively. The crystals of the enzyme-L-kynurenine complex belong to the space group P2(1) with 1 enzyme molecule in the asymmetric unit. The crystal structure of the enzymeL-kynurenine-Ro61-8048 complex belongs to the space group P2(1)2(1)2(1) with 1 pfKMO molecule in the asymmetric unit. The crystal structure of the SeMet enzyme derivative belongs to the space group P2(1) with 2 enzyme molecules in the asymmetric unit
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E372A
about 15% of the enzyme activity compared with that of the wild-type enzyme
E372Q
about 5% of the enzyme activity compared with that of the wild-type enzyme
M373L
about 60% of the enzyme activity compared with that of the wild-type enzyme
N369A
about 65% of the enzyme activity compared with that of the wild-type enzyme
Q424A
mutation does not greatly affect enzyme activity. Ro 61-8048 shows no inhibition to the pfKMO mutant enzyme
Y404F
about 40% of the enzyme activity compared with that of the wild-type enzyme
Y98F
about 1% of the enzyme activity compared with that of the wild-type enzyme
additional information
generation of a C-terminal domain truncated human KMO whose membrane targeting sequence in its C-terminal domain is suggested to be an essential part of its catalysis
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
disulfide reductants like dithiothreitol or 2-mercaptoethanol stabilize the enzyme
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme 8.8fold from Escherichia coli strain by ammonium sulfate fractionation and ion exchange chromatography to homogeneity
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
medicine
inhibition of the enzyme shows benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. It is a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS)
medicine
-
the enzyme is an attractive target for the treatment of ischemic stroke
drug development
enzyme KMO is an important drug target due to its role in regulating the levels of bioactive substances with contrasting effects. For treatment of central nervous related diseases, it is required that enzyme inhibitors should be both blood brain barrier permeable and should not cause hydrogen peroxide as a harmful side product. Molecular dynamics simulations and MM/GBSA calculations, overview
drug development
KMO has been identified as a therapeutic target for limiting neuronal damage from ischemia and specific diseases. The inhibition of KMO in vivo has synergistic neuroprotective effects that include elevation of the concentration of kynurenate, that both slows glutamate release and antagonizes NMDA receptors, reducing aberrant excitation. Inhibition of KMO also has the added benefit of halting the accumulation of specific neurotoxic and/or apoptotic metabolites, such as 3-hydroxy-L-kynurenine and quinolinic acid
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Crozier, K.R.; Moran, G.R.
Heterologous expression and purification of kynurenine-3-monooxygenase from Pseudomonas fluorescens strain 17400
Protein Expr. Purif.
51
324-333
2007
Pseudomonas fluorescens, Pseudomonas fluorescens 17400
Crozier-Reabe, K.R.; Phillips, R.S.; Moran, G.R.
Kynurenine 3-monooxygenase from Pseudomonas fluorescens: substrate-like inhibitors both stimulate flavin reduction and stabilize the flavin-peroxo intermediate yet result in the production of hydrogen peroxide
Biochemistry
47
12420-12433
2008
Pseudomonas fluorescens
Smith, J.R.; Jamie, J.F.; Guillemin, G.J.
Kynurenine-3-monooxygenase a review of structure, mechanism, and inhibitors
Drug Discov. Today
21
315-324
2016
Homo sapiens (O15229), Rattus norvegicus (O88867), Pseudomonas fluorescens (Q84HF5), Sus scrofa (Q9MZS9)
Gao, J.; Yao, L.; Xia, T.; Liao, X.; Zhu, D.; Xiang, Y.
Biochemistry and structural studies of kynurenine 3-monooxygenase reveal allosteric inhibition by Ro 61-8048
FASEB J.
32
2036-2045
2017
Homo sapiens (O15229), Homo sapiens, Pseudomonas fluorescens (Q84HF5), Pseudomonas fluorescens
Walker, A.L.; Ancellin, N.; Beaufils, B.; Bergeal, M.; Binnie, M.; Bouillot, A.; Clapham, D.; Denis, A.; Haslam, C.P.; Holmes, D.S.; Hutchinson, J.P.; Liddle, J.; McBride, A.; Mirguet, O.; Mowat, C.G.; Rowland, P.; Tiberghien, N.; Trottet, L.; Uings, I.; Webster, S.P.; Zheng, X.; Mole, D.J.
Development of a series of kynurenine 3-monooxygenase inhibitors leading to a clinical candidate for the treatment of acute pancreatitis
J. Med. Chem.
60
3383-3404
2017
Pseudomonas fluorescens (Q84HF5)
Hutchinson, J.P.; Rowland, P.; Taylor, M.R.D.; Christodoulou, E.M.; Haslam, C.; Hobbs, C.I.; Holmes, D.S.; Homes, P.; Liddle, J.; Mole, D.J.; Uings, I.; Walker, A.L.; Webster, S.P.; Mowat, C.G.; Chung, C.W.
Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase
Nat. Commun.
8
15827
2017
Homo sapiens (O15229), Pseudomonas fluorescens (Q84HF5)
Beaupre, B.A.; Reabe, K.R.; Roman, J.V.; Moran, G.R.
Hydrogen movements in the oxidative half-reaction of kynurenine 3-monooxygenase from Pseudomonas fluorescens reveal the mechanism of hydroxylation
Arch. Biochem. Biophys.
690
108474
2020
Pseudomonas fluorescens (Q84HF5), Pseudomonas fluorescens
Oezkilic, Y.; Tuezuen, N.S.
In silico methods predict new blood-brain barrier permeable structure for the inhibition of kynurenine 3-monooxygenase
J. Mol. Graph. Model.
100
107701
2020
Homo sapiens (O15229), Saccharomyces cerevisiae (P38169), Pseudomonas fluorescens (Q84HF5)
Oezkilic, Y.; Tuezuen, N.S.
Mechanism of kynurenine 3-monooxygenase-catalyzed hydroxylation reaction a quantum cluster approach
J. Phys. Chem. A
123
3149-3159
2019
Pseudomonas fluorescens (Q84HF5)
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