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 | 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 | 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 | 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 | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | A0A024R3S9 | - |
- |
Mus musculus | Q91WN4 | - |
- |
Rattus norvegicus | O88867 | - |
- |
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 | 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 | 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 | 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 | 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 |