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Information on EC 1.14.13.9 - kynurenine 3-monooxygenase and Organism(s) Saccharomyces cerevisiae and UniProt Accession P38169

for references in articles please use BRENDA:EC1.14.13.9
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IUBMB Comments
A flavoprotein (FAD).
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This record set is specific for:
Saccharomyces cerevisiae
UNIPROT: P38169
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Word Map
The taxonomic range for the selected organisms is: Saccharomyces cerevisiae
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
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
FAD dependent kynurenine 3-monooxygenase
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flavin adenine dinucleotide dependent kynurenine 3-monooxygenase
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kynurenine 3-hydroxylase
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-
-
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kynurenine hydroxylase
-
-
-
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L-kynurenine-3-hydroxylase
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-
-
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oxygenase, kynurenine 3-mono-
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-
-
-
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
redox reaction
-
-
-
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oxidation
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-
-
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reduction
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-
-
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PATHWAY SOURCE
PATHWAYS
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-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
L-kynurenine,NADPH:oxygen oxidoreductase (3-hydroxylating)
A flavoprotein (FAD).
CAS REGISTRY NUMBER
COMMENTARY hide
9029-61-2
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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
-
rate limiting step in the pyridine nucleotide biosynthesis from tryptophan
-
-
?
additional information
?
-
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
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
-
step in L-tryptophan catabolism, overview
-
-
?
L-kynurenine + NADPH + O2
? + NADP+
show the reaction diagram
-
rate limiting step in the pyridine nucleotide biosynthesis from tryptophan
-
-
?
additional information
?
-
-
the enzyme is a very potent suppressor of toxicity of a fragment of the protein huntingtin, Htt, which causes the neurodegenerative Huntington disease in humans by aggregation in nuclear and cytoplasmic inclusion bodies
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
less effective than NADPH
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
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-(3,4-dichlorobenzoyl)-cyclopropane-1-carboxylic acid
UPF648, UPF648 prevents the binding of the native substrate KYN by binding closely to the FAD cofactor. Enzyme-binding structure determination (PDB ID 4J36) and further pharmacophore modeling
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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. Ro 61-8048-scKMO complex structure analysis
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3,4-dimethoxyhippuric acid
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CHDI-340246
CHDI-340246-scKMO complex structure analysis
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UPF 648
UPF 648 binds close to the FAD cofactor and perturbs the local active site structure, preventing productive binding of the substrate kynurenine
3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide
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i.e. Ro 61-8048, high-affinity low molecular inhibitor
NADH
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above 3 mM
p-chloromercuribenzoate
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weak, 50% inhibition at 0.4 M
additional information
enzyme structure and ligand interaction analysis using the crystal structure of scKMO (PDB ID 4J34), library screening from Zinc15 database, detailed overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.04 - 0.045
L-kynurenine
0.016 - 0.017
NADPH
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.033
3,4-dimethoxyhippuric acid
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000074
UPF 648
Saccharomyces cerevisiae
pH 8.0, 30°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.1 - 8.9
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about 50% of maximal activity at pH 7.1 and 8.9
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
metabolism
physiological function
additional information
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
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
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in baculoviral system
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
McLean-Bowen, C.A.; Parks, L.W.
Corresponding changes in kynurenine hydroxylase activity, membrane fluidity, and sterol composition in Saccharomyces cerevisiae mitochondria
J. Bacteriol.
145
1325-1333
1981
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Schott, H.H.; Staudinger, H.
The regulatory function of L-kynurenine 3-hydroxylase (EC 1.14.1.2) for the biosynthesis of pyridine nucleotides in anaerobically and aerobically grown Saccharomyces cerevisiae
Hoppe-Seyler's Z. Physiol. Chem.
352
1654-1658
1971
Saccharomyces cerevisiae
Manually annotated by BRENDA team
Giorgini, F.; Guidetti, P.; Nguyen, Q.; Bennett, S.C.; Muchowski, P.J.
A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease
Nat. Genet.
37
526-531
2005
Saccharomyces cerevisiae, Homo sapiens
Manually annotated by BRENDA team
Amaral, M.; Levy, C.; Heyes, D.J.; Lafite, P.; Outeiro, T.F.; Giorgini, F.; Leys, D.; Scrutton, N.S.
Structural basis of kynurenine 3-monooxygenase inhibition
Nature
496
382-385
2013
Saccharomyces cerevisiae (P38169), Saccharomyces cerevisiae
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
Hughes, T.D.; Guener, O.F.; Iradukunda, E.C.; Phillips, R.S.; Bowen, J.P.
The kynurenine pathway and kynurenine 3-monooxygenase inhibitors
Molecules
27
273
2022
Homo sapiens (O15229), Saccharomyces cerevisiae (P38169), Pseudomonas fluorescens (Q84HF5), Mus musculus (Q91WN4)
Manually annotated by BRENDA team