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Literature summary for 1.14.13.9 extracted from

  • Oezkilic, Y.; Tuezuen, N.S.
    In silico methods predict new blood-brain barrier permeable structure for the inhibition of kynurenine 3-monooxygenase (2020), J. Mol. Graph. Model., 100, 107701 .
    View publication on PubMed

Application

Application Comment Organism
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 Saccharomyces cerevisiae
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 Pseudomonas fluorescens
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 Homo sapiens

Protein Variants

Protein Variants Comment Organism
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 Saccharomyces cerevisiae
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 Pseudomonas fluorescens
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 Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzene-1-sulfonamide Ro 61-8048 Homo sapiens
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 Pseudomonas fluorescens
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 Saccharomyces cerevisiae
CHDI-340246 CHDI-340246-scKMO complex structure analysis Saccharomyces cerevisiae
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 Pseudomonas fluorescens
additional information enzyme structure and ligand interaction analysis using the crystal structure of hKMO (PDB ID 5X68), library screening from Zinc15 database, detailed overview Homo sapiens
additional information enzyme structure and ligand interaction analysis using the crystal structure of pfKMO (PDB ID 5NAK), library screening from Zinc15 database, detailed overview Pseudomonas fluorescens
additional information enzyme structure and ligand interaction analysis using the crystal structure of scKMO (PDB ID 4J34), library screening from Zinc15 database, detailed overview Saccharomyces cerevisiae
ZINC19827377 the inhibitor does not cause hydrogen peroxide as a harmful side product Homo sapiens
ZINC19827377
-
Pseudomonas fluorescens
ZINC19827377
-
Saccharomyces cerevisiae
ZINC71915355 the inhibitor is both blood brain barrier permeable and does not cause hydrogen peroxide as a harmful side product Homo sapiens
ZINC71915355
-
Pseudomonas fluorescens
ZINC71915355
-
Saccharomyces cerevisiae

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrial outer membrane
-
Homo sapiens 5741
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
L-kynurenine + NADPH + H+ + O2 Saccharomyces cerevisiae
-
3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2 Pseudomonas fluorescens
-
3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2 Homo sapiens
-
3-hydroxy-L-kynurenine + NADP+ + H2O
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens O15229
-
-
Pseudomonas fluorescens Q84HF5
-
-
Saccharomyces cerevisiae P38169
-
-

Reaction

Reaction Comment Organism Reaction ID
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 Saccharomyces cerevisiae
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 Pseudomonas fluorescens
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 Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
central nervous system
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
L-kynurenine + NADPH + H+ + O2
-
Saccharomyces cerevisiae 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2
-
Pseudomonas fluorescens 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2
-
Homo sapiens 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
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 Pseudomonas fluorescens ?
-
-
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. UPF-648 for enzyme scKMO. 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 Saccharomyces cerevisiae ?
-
-
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. 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 Homo sapiens ?
-
-

Subunits

Subunits Comment Organism
More 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 Saccharomyces cerevisiae
More 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 Pseudomonas fluorescens
More 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 Homo sapiens

Synonyms

Synonyms Comment Organism
FAD dependent kynurenine 3-monooxygenase
-
Saccharomyces cerevisiae
FAD dependent kynurenine 3-monooxygenase
-
Pseudomonas fluorescens
FAD dependent kynurenine 3-monooxygenase
-
Homo sapiens
flavin adenine dinucleotide dependent kynurenine 3-monooxygenase
-
Saccharomyces cerevisiae
flavin adenine dinucleotide dependent kynurenine 3-monooxygenase
-
Pseudomonas fluorescens
flavin adenine dinucleotide dependent kynurenine 3-monooxygenase
-
Homo sapiens
hKMO
-
Homo sapiens
KMO
-
Saccharomyces cerevisiae
KMO
-
Pseudomonas fluorescens
KMO
-
Homo sapiens
pfKMO
-
Pseudomonas fluorescens
scKMO
-
Saccharomyces cerevisiae

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
assay at Homo sapiens

Cofactor

Cofactor Comment Organism Structure
FAD
-
Saccharomyces cerevisiae
FAD
-
Pseudomonas fluorescens
FAD
-
Homo sapiens
NADPH
-
Saccharomyces cerevisiae
NADPH
-
Pseudomonas fluorescens
NADPH
-
Homo sapiens

General Information

General Information Comment Organism
malfunction hKMO is inactive without its membrane targeting domain Homo sapiens
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 Saccharomyces cerevisiae
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 Homo sapiens
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 Pseudomonas fluorescens
additional information PfKMO is active without its membrane targeting domain, structure comparisons with the enzymes from Saccharomyces cerevisiae and Homo sapiens, overview Pseudomonas fluorescens
additional information ScKMO is active without its membrane targeting domain, structure comparisons with the enzymes from Homo sapiens (hKMO) and Pseudomonas fluorescens (pfKMO), overview Saccharomyces cerevisiae
additional information structure comparisons with the enzymes from Saccharomyces cerevisiae (scKMO) and Pseudomonas fluorescens (pfKMO), overview Homo sapiens
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 Saccharomyces cerevisiae
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 Pseudomonas fluorescens
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. High levels of these substances correlate with the neurodegenerative diseases (Huntington's, Alzheimer's, and Parkinson's) Homo sapiens