Application | Comment | Organism |
---|---|---|
diagnostics | the upregulation of KMO currently serves as an independent prognostic biomarker to identify certain liver malignancies, particularly hepatocellular carcinoma (HCC). HCC patients who express increased KMO activity are known to have unfavorable clinical outcomes compared to those who do not. The upregulation of KMO also plays a critical role in triple-negative breast cancer progression and metastasis. The pharmacological inhibition of KMO with GSK180 granted therapeutic protection in acute pancreatitis rodent models preventing multiple organ failures | Homo sapiens |
drug development | the enzyme is a target for drug development in neurological, but also other, diseases, pharmacophore development with receptor-based pharmacophore modeling, detailed overview | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
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. In a transgenic Drosophila melanogaster model of Huntington's disease, UPF648 is shown to mitigate disease-relevant phenotypes. While UPF648 inhibits KMO, it also significantly increases the production of hydrogen peroxide by almost 20fold | Homo sapiens | |
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 | Saccharomyces cerevisiae | |
3,4-dichlorobenzoyl alanine | 3,4-CBA or FCE 28833, a substrate analogue | Homo sapiens | |
3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide | Ro-61-8048, shows a greater potency than the previously discussed native substrate analogue 3,4-dichlorobenzoyl alanine | Homo sapiens | |
3,4-dimethoxyhippuric acid | - |
Saccharomyces cerevisiae | |
4-amino-N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfonamide | - |
Homo sapiens | |
ianthellamide A | an octopamine derivative isolated from the Australian marine sponge Ianthella quadrangulata, selectively inhibits KMO | Homo sapiens | |
additional information | research focuses on the inhibition of key enzymes in the kynurenine pathway (KP) to shunt it towards a neuroprotective state, based on the assumption that kynurenic acid (KYNA) has neuroprotective abilities. While substrate analogues bind in the active site of KMO and inhibit activity, they also detrimentally result in the formation of cytotoxic hydrogen peroxide by uncoupling the reaction of NAD(P)H and O2 | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
mitochondrial outer membrane | - |
Homo sapiens | 5741 | - |
mitochondrial outer membrane | - |
Mus musculus | 5741 | - |
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 | - |
? | |
L-kynurenine + NADPH + H+ + O2 | Mus musculus | - |
3-hydroxy-L-kynurenine + NADP+ + H2O | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | O15229 | - |
- |
Mus musculus | Q91WN4 | - |
- |
Pseudomonas fluorescens | Q84HF5 | - |
- |
Saccharomyces cerevisiae | P38169 | - |
- |
Reaction | Comment | Organism | Reaction ID |
---|---|---|---|
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O | catalytic reaction mechanism, overview | Saccharomyces cerevisiae | |
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O | catalytic reaction mechanism, overview | Pseudomonas fluorescens | |
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O | catalytic reaction mechanism, overview | Homo sapiens | |
L-kynurenine + NADPH + H+ + O2 = 3-hydroxy-L-kynurenine + NADP+ + H2O | catalytic reaction mechanism, overview | Mus musculus |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
brain | - |
Homo sapiens | - |
brain | - |
Mus musculus | - |
kidney | - |
Homo sapiens | - |
kidney | - |
Mus musculus | - |
liver | - |
Homo sapiens | - |
liver | - |
Mus musculus | - |
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 | - |
? | |
L-kynurenine + NADPH + H+ + O2 | - |
Mus musculus | 3-hydroxy-L-kynurenine + NADP+ + H2O | - |
? |
Synonyms | Comment | Organism |
---|---|---|
KMO | - |
Saccharomyces cerevisiae |
KMO | - |
Pseudomonas fluorescens |
KMO | - |
Homo sapiens |
KMO | - |
Mus musculus |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
FAD | - |
Saccharomyces cerevisiae | |
FAD | - |
Pseudomonas fluorescens | |
FAD | - |
Homo sapiens | |
FAD | - |
Mus musculus | |
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 | Saccharomyces cerevisiae | |
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 | Pseudomonas fluorescens | |
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 | Homo sapiens | |
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 | Mus musculus | |
NADH | - |
Saccharomyces cerevisiae | |
NADH | - |
Pseudomonas fluorescens | |
NADH | - |
Homo sapiens | |
NADH | - |
Mus musculus | |
NADPH | - |
Saccharomyces cerevisiae | |
NADPH | - |
Pseudomonas fluorescens | |
NADPH | - |
Homo sapiens | |
NADPH | - |
Mus musculus |
Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
---|---|---|---|---|---|
0.033 | - |
3,4-dimethoxyhippuric acid | pH and temperature not specified in the publication | Saccharomyces cerevisiae |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.000019 | - |
pH and temperature not specified in the publication | Homo sapiens | 4-amino-N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfonamide | |
0.000037 | - |
pH and temperature not specified in the publication | Homo sapiens | 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide | |
0.0015 | - |
pH and temperature not specified in the publication | Homo sapiens | ianthellamide A |
General Information | Comment | Organism |
---|---|---|
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 | Saccharomyces cerevisiae |
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 | Pseudomonas fluorescens |
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 | Homo sapiens |
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 | Mus musculus |
malfunction | the dysregulation of the kynurenine pathway and increased levels of toxic metabolites have been implicated in various disease states, including neurological disorders such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) epilepsy, affective disorders schizophrenia, depression, and anxiety, autoimmune related diseases rheumatoid arthritis (RA), multiple sclerosis (MS), and HIV-related dementia, peripheralconditions such as cardiovascular disease and ischemic stroke, and malignancies such as hematological neoplasia and colorectal cancer. The inhibition of KMO is a potential therapeutic strategy to rebalance the KP in hopes of mitigating and/or preventing disease progression since it sits at the key branching point of the KP. Inhibiting KMO will not only decrease the levels of toxic metabolites 3-HK and QUIN, but also increase the levels of the neuroprotective KYNA available for metabolism by kynurenine aminotransferase. Mechanisms, overview | Homo sapiens |
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 | Saccharomyces cerevisiae |
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 | Pseudomonas fluorescens |
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 | Mus musculus |
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. KYNA serves as a neuroprotective agent due to its antagonistic effects at the glutamate receptor and all three subtypes of ionotropic receptors, N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). KYNA selectively binds to a G-protein-coupled receptor, GPR35, leading to its activation. Also, kynurenic acid plays a role in epilepsy and has ability to reduce ischemic brain damage. KYNA also has antioxidant properties, as it can scavenge hydroxyl, superoxide anion, and other free radicals. Patients with schizophrenia presented with elevated kynurenic acid levels in the cerebral spinal fluid. Elevated levels of endogenous kynurenic acid increase the firing activity of midbrain dopamine neurons. This increase alters the effects of both nicotine and clozapine, leading to inhibitory responses of the ventral tegmental area (VTA) dopamine neurons that cause disrupted prepulse inhibition, an effect restored by antipsychotics. Elevated levels of KYNA have also been implicated in rapid progression among lung cancer patients, HIV-related illnesses, cataracts, tick-borne encephalitis, and partial seizures in epileptic patients. Most recently, KYNA has also been associated with antidepressant-like and antimigraine-like effects as well. Other endogenous neuroprotectant metabolites of the kynurenine pathway, detailed overview. Research focuse on the inhibition of key enzymes in the kynurenine pathway (KP) to shunt it towards a neuroprotective state, based on the assumption that kynurenic acid (KYNA) has neuroprotective abilities. Dissimilar to the other neurotoxic metabolites of the kynurenine pathway, the toxic effects of 3-hydroxykynurenine (3-HK) are independent of the NMDA receptor and solely result from the production of free radicals. 3-HK is mostly known for its ability to filter UV light in the human lens and its involvement in cataract formation. 3-HK is a controversial metabolite, while mostly considered neurotoxic, it is also able to act as a scavenger and is involved in immunoregulation. Similar to 3-HK, 3-hydroxyanthranilic acid (3-HANA) has also been shown to play a role in the regulation of the immune system and is believed to scavenge NO radicals. 3-HANA is prone to autooxidation | Homo sapiens |
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 | Saccharomyces cerevisiae |
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 | Pseudomonas fluorescens |
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 | Homo sapiens |
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 | Mus musculus |
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 | Saccharomyces cerevisiae |
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 | Pseudomonas fluorescens |
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 | Mus musculus |
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. Numerous pathological conditions involve KP, including neurological disorders (e.g., schizophrenia, depression, and anxiety), autoimmune diseases (e.g., multiple sclerosis and rheumatoid arthritis), peripheral conditions (e.g. cardiovascular disease and acute pancreatitis), and neurodegenerative illnesses (e.g., Huntington's disease, Alzheimer's disease, and Parkinson's disease) and HIV | Homo sapiens |