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Literature summary for 1.14.13.9 extracted from

  • Zhang, S.; Collier, M.E.W.; Heyes, D.J.; Giorgini, F.; Scrutton, N.S.
    Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases (2021), Arch. Biochem. Biophys., 697, 108702 .
    View publication on PubMed

Application

Application Comment Organism
drug development importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases Rattus norvegicus
drug development importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases Mus musculus
drug development importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases Homo sapiens
medicine importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases. KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites Rattus norvegicus
medicine importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases. KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites Mus musculus
medicine importance of KMO as a drug target in neurological disease, benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system teeating brain neurological diseases. KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid KMO-inhibitor 1 Homo sapiens
(6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid KMO-inhibitor 1 Mus musculus
(6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid KMO-inhibitor 1 Rattus norvegicus
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 Mus musculus
3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzene-1-sulfonamide Ro 61-8048 Rattus norvegicus
ethyl (6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate KMO-inhibitor 1b, in the ligand structure, the carboxylate group of the inhibitor sits close to residues R83/Y97/N368 in the KMO active site. Several interactions between ligand and protein have been identified Homo sapiens
ethyl (6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate KMO-inhibitor 1b, in the ligand structure, the carboxylate group of the inhibitor sits close to residues R83/Y97/N368 in the KMO active site. Several interactions between ligand and protein have been identified Mus musculus
ethyl (6-chloro-5,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate KMO-inhibitor 1b, in the ligand structure, the carboxylate group of the inhibitor sits close to residues R83/Y97/N368 in the KMO active site. Several interactions between ligand and protein have been identified Rattus norvegicus
additional information KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites. Virtual screening combined with a prodrug strategy are used to develop brain-permeable KMO inhibitors. Prodrugs are considered as one of the most promising technologies for lead compound optimisation to cross the blood-brain barrier. For KMO inhibitors, one of the main challenges to cross the blood-brain barrier is the acidic centre, which mimics the binding of the carboxyl group of L-KYN Homo sapiens
additional information KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites. Virtual screening combined with a prodrug strategy are used to develop brain-permeable KMO inhibitors. Prodrugs are considered as one of the most promising technologies for lead compound optimisation to cross the blood-brain barrier. For KMO inhibitors, one of the main challenges to cross the blood-brain barrier is the acidic centre, which mimics the binding of the carboxyl group of L-KYN Mus musculus
additional information KMO inhibitors with brain permeability would be predicted to be more efficacious for treating neurodegenerative diseases than peripheral treatment, as inhibition of KMO in the CNS leads to increased neuroprotective KYNA levels as well as decreased levels of neurotoxic metabolites. Virtual screening combined with a prodrug strategy are used to develop brain-permeable KMO inhibitors. Prodrugs are considered as one of the most promising technologies for lead compound optimisation to cross the blood-brain barrier. For KMO inhibitors, one of the main challenges to cross the blood-brain barrier is the acidic centre, which mimics the binding of the carboxyl group of L-KYN Rattus norvegicus

Localization

Localization Comment Organism GeneOntology No. Textmining
membrane specifically, KMO is localised to the outer membrane of mitochondria where it associates with the lipid membrane using C-terminal transmembrane domains, which are also crucial for the catalytic activity of KMO Rattus norvegicus 16020
-
membrane specifically, KMO is localised to the outer membrane of mitochondria where it associates with the lipid membrane using C-terminal transmembrane domains, which are also crucial for the catalytic activity of KMO Mus musculus 16020
-
membrane specifically, KMO is localised to the outer membrane of mitochondria where it associates with the lipid membrane using C-terminal transmembrane domains, which are also crucial for the catalytic activity of KMO Homo sapiens 16020
-
microsome
-
Rattus norvegicus
-
-
microsome
-
Mus musculus
-
-
microsome
-
Homo sapiens
-
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
L-kynurenine + NADPH + H+ + O2 Rattus norvegicus
-
3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2 Mus musculus
-
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 A0A024R3S9
-
-
Mus musculus Q91WN4
-
-
Rattus norvegicus O88867
-
-

Source Tissue

Source Tissue Comment Organism Textmining
brain
-
Rattus norvegicus
-
brain
-
Mus musculus
-
brain
-
Homo sapiens
-
kidney
-
Rattus norvegicus
-
kidney
-
Mus musculus
-
kidney
-
Homo sapiens
-
liver
-
Rattus norvegicus
-
liver
-
Mus musculus
-
liver
-
Homo sapiens
-
macrophage
-
Rattus norvegicus
-
macrophage
-
Mus musculus
-
macrophage
-
Homo sapiens
-
microglia
-
Rattus norvegicus
-
microglia
-
Mus musculus
-
microglia
-
Homo sapiens
-
additional information enzyme KMO is expressed in microglia and infiltrating macrophages in the brain, and at high levels in the liver, kidneys and placenta in the periphery Rattus norvegicus
-
additional information enzyme KMO is expressed in microglia and infiltrating macrophages in the brain, and at high levels in the liver, kidneys and placenta in the periphery Mus musculus
-
additional information enzyme KMO is expressed in microglia and infiltrating macrophages in the brain, and at high levels in the liver, kidneys and placenta in the periphery Homo sapiens
-
placenta
-
Rattus norvegicus
-
placenta
-
Mus musculus
-
placenta
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
L-kynurenine + NADPH + H+ + O2
-
Rattus norvegicus 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2
-
Mus musculus 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
L-kynurenine + NADPH + H+ + O2
-
Homo sapiens 3-hydroxy-L-kynurenine + NADP+ + H2O
-
?
additional information following binding of L-KYN to KMO, NADPH acts as an electron donor and reduces FAD, leading to the formation of a L-KYN-FAD-hydroperoxide intermediate. L-KYN is then oxidised, resulting in the release of 3-HK and water Rattus norvegicus ?
-
-
additional information following binding of L-KYN to KMO, NADPH acts as an electron donor and reduces FAD, leading to the formation of a L-KYN-FAD-hydroperoxide intermediate. L-KYN is then oxidised, resulting in the release of 3-HK and water Mus musculus ?
-
-
additional information following binding of L-KYN to KMO, NADPH acts as an electron donor and reduces FAD, leading to the formation of a L-KYN-FAD-hydroperoxide intermediate. L-KYN is then oxidised, resulting in the release of 3-HK and water Homo sapiens ?
-
-

Synonyms

Synonyms Comment Organism
KMO
-
Rattus norvegicus
KMO
-
Mus musculus
KMO
-
Homo sapiens
kynurenine-3-monooxygenase
-
Rattus norvegicus
kynurenine-3-monooxygenase
-
Mus musculus
kynurenine-3-monooxygenase
-
Homo sapiens
NADPH-dependent flavin monooxygenase
-
Rattus norvegicus
NADPH-dependent flavin monooxygenase
-
Mus musculus
NADPH-dependent flavin monooxygenase
-
Homo sapiens

Cofactor

Cofactor Comment Organism Structure
FAD cofactor flavin adenine dinucleotide (FAD) binds to KMO at a 1:1 ratio Rattus norvegicus
FAD cofactor flavin adenine dinucleotide (FAD) binds to KMO at a 1:1 ratio Mus musculus
FAD cofactor flavin adenine dinucleotide (FAD) binds to KMO at a 1:1 ratio Homo sapiens
NADPH
-
Rattus norvegicus
NADPH
-
Mus musculus
NADPH
-
Homo sapiens

General Information

General Information Comment Organism
malfunction kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders. Potent inhibitors of KMO within different disease models show great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid Rattus norvegicus
malfunction kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders. Potent inhibitors of KMO within different disease models show great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid Mus musculus
malfunction kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders. Potent inhibitors of KMO within different disease models show great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid Homo sapiens
metabolism KMO is an important enzyme in the kynurenine pathway (KP), overview. The KP metabolises more than 95% of TRP. This pathway has been implicated in numerous diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease, schizophrenia, acute pancreatitis and cancer. L-kynurenine (L-KYN) can be metabolised by three different enzymes and lies at the key branchpoint of the KP. L-KYN can be metabolised to 3-hydroxy-L-kynurenine (3-HK) by KMO, or it can form kynurenic acid (KYNA), by a transamination reaction catalysed by kynurenine aminotransferase II (KATII), or alternatively it can be converted to anthranilic acid (AA) by kynureninase, which then feeds back into the 3-HK branch of the KP. Since KMO has the tightest binding affinity for L-KYN under normal conditions, the KMO branch has been considered to be the major metabolic route of the KP. KMO activity plays an essential role in maintaining a balance between the neurotoxic and neuroprotective potential of the pathway Rattus norvegicus
metabolism KMO is an important enzyme in the kynurenine pathway (KP), overview. The KP metabolises more than 95% of TRP. This pathway has been implicated in numerous diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease, schizophrenia, acute pancreatitis and cancer. L-kynurenine (L-KYN) can be metabolised by three different enzymes and lies at the key branchpoint of the KP. L-KYN can be metabolised to 3-hydroxy-L-kynurenine (3-HK) by KMO, or it can form kynurenic acid (KYNA), by a transamination reaction catalysed by kynurenine aminotransferase II (KATII), or alternatively it can be converted to anthranilic acid (AA) by kynureninase, which then feeds back into the 3-HK branch of the KP. Since KMO has the tightest binding affinity for L-KYN under normal conditions, the KMO branch has been considered to be the major metabolic route of the KP. KMO activity plays an essential role in maintaining a balance between the neurotoxic and neuroprotective potential of the pathway Mus musculus
metabolism KMO is an important enzyme in the kynurenine pathway (KP), overview. The KP metabolises more than 95% of TRP. This pathway has been implicated in numerous diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease, schizophrenia, acute pancreatitis and cancer. L-kynurenine (L-KYN) can be metabolised by three different enzymes and lies at the key branchpoint of the KP. L-KYN can be metabolised to 3-hydroxy-L-kynurenine (3-HK) by KMO, or it can form kynurenic acid (KYNA), by a transamination reaction catalysed by kynurenine aminotransferase II (KATII), or alternatively it can be converted to anthranilic acid (AA) by kynureninase, which then feeds back into the 3-HK branch of the KP. Since KMO has the tightest binding affinity for L-KYN under normal conditions, the KMO branch has been considered to be the major metabolic route of the KP. KMO activity plays an essential role in maintaining a balance between the neurotoxic and neuroprotective potential of the pathway Homo sapiens