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Kynurenine 3-monooxygenase

March 08, 2024

In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

kynurenine 3-monooxygenase
Structure of the kynurenine 3-monooxygenase dimer, generated from 4J34.[1] One monomer is depicted in cartoon format (cyan) and the second monomer is displayed in ribbon format (green). The flexible linker regions (residues 96-104) are colored red. Flavin adenine dinucleotide (FAD) is shown as spheres color-coded according to atom type.
Identifiers
EC no.1.14.13.9
CAS no.9029-61-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
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L-kynurenine + NADPH + H+ + O2 ⇌ 3-hydroxy-L-kynurenine + NADP+ + H2O

Kynurenine 3-monooxygenase is the expression product of the KMO (gene). The systematic name of this enzyme class is L-kynurenine, NADPH:oxygen oxidoreductase (3-hydroxylating). Other names in common use include kynurenine 3-hydroxylase, kynurenine hydroxylase, and L-kynurenine-3-hydroxylase. It participates in tryptophan metabolism through the kynurenine catabolic pathway. This enzyme belongs to the family of oxidoreductases, to be specific, those acting on paired donors, with O2 as the oxidant. Kynurenine 3-monooxygenase catalyzes the insertion of molecular oxygen into the aromatic ring of kynurenine to produce 3-hydroxy-L-kynurenine.[2] It employs one cofactor, FAD. Kynurenine 3-monooxygenase serves as an important branch point in the kynurenine pathway and, as a result, is an attractive drug target for immunological, neurodegenerative, and neuroinflammatory diseases.[3] Currently, most research on the kynurenine 3-monooxygenase enzyme has been focused primarily on rat models[4] and in yeast,[5] both of which have been demonstrated to have high sequence homology with the human kynurenine 3-monooxygenase protein. Studies have shown the beneficial effects of enzyme inhibition in these eukaryotic kynurenine 3-monooxygenase active sites, thus making this enzyme an attractive target for human drug design.[3][5]

Structure edit

Kynurenine 3-monooxygenase is a dimer containing asymmetric subunits[5] and has one FAD-binding domain as its prosthetic group.[3] Kynurenine 3-monooxygenase contains a linker region involved in substrate binding following a second strand of an antiparallel β-sheet, a six-stranded antiparallel β-sheet domain, and an α-helix at the carboxy-terminal.[5] The hydrophobic C-terminus acts as the mitochondrial anchoring domain and participates in enzymatic activity.[6]

Active site edit

While no scientific literature reports a crystal image of a kynurenine 3-monooxygenase complex with L-kynurenine, structural studies of the enzyme in yeast co-crystallized with UPF 648 reveal how the FAD cofactor and substrate are bound in the active site.[1] Chemical similarities between UPF 648 and L-kynurenine suggest that the substrate binds adjacent to the Re-face of the flavoprotein. A loop containing the residues Pro321–Gln325 is believed to be the oxygen-binding site above the re-side of the FAD prosthetic group.[5]

Each monomer contains a conserved hydrophobic pocket (residues Leu221, Met230, Ile232, Leu234, Phe246, Pro321, Phe322) positioned around the substrate’s aromatic benzene moiety.[5] A conserved Gln325 polar residue is also involved in hydrogen bonding on the L-kynurenine carbonyl group, as well as on the hydrogen on the FAD N3 atom.[1] Arg83 and Tyr97 also form polar contacts with the carboxylate in the amino acid moiety on the substrate.[7]

Mechanism edit

Kynurenine-3-monooxygenase catalyzes the hydroxylation of L-kynurenine to 3-hydroxy-L-kynurenine with concomitant interconversion of NADPH to NADP+. The reaction mechanism is not entirely known, but is believed to follow mechanisms related to the flavin-dependent monooxygenases.[8] After L-kynurenine binds, NADPH reduces FAD and leaves as NADP+. Oxygen then binds and creates an L-kynurenine-FAD-hydroperoxide intermediate.[5][9] This intermediate is the electrophilic source for the hydroxylation reaction, yielding a primary ketimine form of the product and the C4a-hydroxy-FAD.[10] Tautomerization yields 3-hydroxy-L-kynurenine in complex with the enzyme (E Fl HOH-P). Dissociation of 3-hydroxy-L-kynurenine and H2O leads to the free enzyme (E Flox).

 
The mechanism of kynurenine 3-monooxygenase[5][9][10] FAD is shown in blue. The substrate, intermediate, and product are depicted in black.

Biological function edit

Kynurenine 3-monooxygenase catalyzes the conversion of L-kynurenine to 3-hydroxy-L-kynurenine, an important bioactive metabolite in the kynurenine pathway. The kynurenine pathway is responsible for over 95% of tryptophan oxidative degradation.[11] L-Kynurenine is an important branch point of this metabolic pathway, being converted into the neurotoxin 3-hydroxy-L-kynurenine via kynurenine 3-monooxygenase, the neuroprotectant kynurenic acid through kynurenine amino transferases, or anthranilic acid by kynureninase.[12]

Kynurenine 3-monooxygenase regulates the downstream production of quinolinic acid, which can generate reactive free radicals[13] and activates the NMDA subtype of glutamate receptors, producing excitotoxic lesions in the central nervous system of mammals.[14][15] Quinolinic acid is also the bioprecursor of NAD+.[12]

Inhibition of kynurenine 3-monooxygenase leads to an increase of kynurenic acid in the kynurenine pathway. This metabolite functions as an antagonist of the α7 nicotinic acetylcholine receptor and as an antagonist at the glycine site of the NMDA receptor.[16] As a result, regulation at the kynurenine 3-monooxygenase enzyme determines the neurotoxic and neuroprotective potential of the kynurenine pathway.

Disease relevance edit

Kynurenine 3-monooxygenase is an attractive drug target for several neurodegenerative and neuroinflammatory diseases, especially Huntington's, Alzheimer's, and Parkinson's disease. Administration of potent enzyme inhibitors has demonstrated promising pharmacological results.[3][5] Specifically, genetic elimination of the kynurenine 3-monooxygenase enzyme has been shown to suppress toxicity of the huntingtin protein in yeast[17] and Drosophila[18] models of Huntington's disease.

Kynurenine 3-monooxygenase deficiency, which can be caused by genetic polymorphisms, cytokines, or both,[19] leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid. Recent research suggests that hyperphysiologic concentrations of kynurenine in kynurenine 3-monooxygenase-deficient patients results in a shift towards kynurenic acid production, believed to be related to cognitive deficits in predictive pursuit and visuospatial working memory.[20] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.[21][22][23][24][25]

References edit

  1. ^ a b c Amaral, M. (2014). "Crystal Structure of kynurenine 3-monooxygenase – truncated at position 394 plus HIS tag cleaved". doi:10.2210/pdb4j34/pdb. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ Filippini, Graziella Allegri; Costa, Carlo V. L.; Bertazzo, Antonella; International Meeting on Tryptophan Research (1998). Recent advances in tryptophan research : tryptophan and serotonin pathways. Advances in Experimental Medicine and Biology. Vol. 398. doi:10.1007/978-1-4613-0381-7. ISBN 978-1-4613-8026-9. S2CID 38080353.
  3. ^ a b c d Smith, Jason R.; Jamie, Joanne F.; Guillemin, Gilles J. (February 2016). "Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors". Drug Discovery Today. 21 (2): 315–324. doi:10.1016/j.drudis.2015.11.001. ISSN 1359-6446. PMID 26589832.
  4. ^ Horn, U.; Ullrich, V.; Staudinger, H.J (1971). "Purification and characterization of L-kynurenine 3-hydroxylase (EC 1.14.1.2.) from rat liver". Hoppe-Seyler's Z. Physiol. Chem. 352 (6): 837–842. doi:10.1515/bchm2.1971.352.1.837. PMID 5087636.
  5. ^ a b c d e f g h i Amaral, M; Levy, C; Heyes, DJ; Lafite, P; Outeiro, TF; Giorgini, F; Leys, D; Scrutton, NS (2013). "Structural basis of kynurenine 3-monooxygenase inhibition". Nature. 496 (7445): 382–385. Bibcode:2013Natur.496..382A. doi:10.1038/nature12039. PMC 3736096. PMID 23575632.
  6. ^ Hirai KH, et al. (2010). "Dual role of the carboxyl-terminal region of pig liver L-kynurenine 3-monooxygenase: mitochondrial-targeting signal and enzymatic activity". J. Biochem. 148 (6): 639–650. doi:10.1093/jb/mvq099. PMID 20802227.
  7. ^ Mole D, et al. (2016). "Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis". Nature Medicine. 22 (2): 202–209. doi:10.1038/nm.4020. PMC 4871268. PMID 26752518.
  8. ^ Breton, J.; et al. (2000). "Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase". Eur. J. Biochem. 267 (4): 1092–1099. doi:10.1046/j.1432-1327.2000.01104.x. PMID 10672018.
  9. ^ a b Crozier-Reabe, KR; et al. (2008). "Kynurenine 3-monooxygenase from Pseudomonas fluorescens: substrate-like inhibitors both stimulate flavin reduction and stabilize the flavin-peroxo intermediate yet result in the production of hydrogen peroxide". Biochemistry. 47 (47): 12420–12433. doi:10.1021/bi8010434. PMID 18954092.
  10. ^ a b Entsch B, et al. (1976). "Flavin-oxygen derivatives involved in the hydroxylation of p-hydroxybenzoate hydroxylase". J. Biol. Chem. 251 (9): 2550–2563. doi:10.1016/S0021-9258(17)33523-8. PMID 816794.
  11. ^ Thevandavakkam MA, et al. (2010). "Targeting kynurenine 3-monooxygenase (KMO). Implications for therapy in Huntington's disease". CNS Neurol. Disord. Drug Targets. 9 (6): 791–800. doi:10.2174/187152710793237430. PMID 20942784.
  12. ^ a b Giorgini F, Huang SY, Sathyasaikumar KV, et al. (2013). "Targeted Deletion of Kynurenine 3-Monooxygenase in Mice: A New Tool for Studying Kynurenine Pathway Metabolism in Periphery and Brain". The Journal of Biological Chemistry. 288 (51): 36554–36566. doi:10.1074/jbc.M113.503813. PMC 3868768. PMID 24189070.
  13. ^ Rios, C.; Santamaria, A. (1991). "Quinolinic acid is a potent lipid peroxidant in rat brain homogenates". Neurochem. Res. 16 (10): 1139–1143. doi:10.1007/bf00966592. PMID 1686636. S2CID 28669340.
  14. ^ Stone, T. W.; Perkins, M. N. (1981). "Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS". Eur. J. Pharmacol. 72 (4): 411–412. doi:10.1016/0014-2999(81)90587-2. PMID 6268428.
  15. ^ Schwarcz, R.; Bruno, J. P.; Muchowski, P. J.; Wu, H. Q. (2012). "Kynurenines in the mammalian brain. When physiology meets pathology". Nat. Rev. Neurosci. 13 (7): 465–477. doi:10.1038/nrn3257. PMC 3681811. PMID 22678511.
  16. ^ Hilmas, C.; Pereira, E. F.; Alkondon, M.; Rassoulpour, A.; Schwarcz, R.; Albuquerque, E. X. (2001). "The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression:Physiopathological implications". J. Neurosci. 21 (19): 7463–7473. doi:10.1523/JNEUROSCI.21-19-07463.2001. PMC 6762893. PMID 11567036.
  17. ^ Giorgini, F.; Guidetti, P.; Nguyen, Q.; Bennett, S. C.; Muchowski, P. J. (2005). "A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease". Nat. Genet. 37 (5): 526–531. doi:10.1038/ng1542. PMC 1449881. PMID 15806102.
  18. ^ Campesan, S.; Green, E. W.; Breda, C.; Sathyasaikumar, K. V.; Muchowski, P. J.; Schwarcz, R.; Kyriacou, C. P.; Giorgini, F (2011). "The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease". Curr. Biol. 21 (11): 961–966. doi:10.1016/j.cub.2011.04.028. PMC 3929356. PMID 21636279.
  19. ^ Müller, N; Myint, AM; Schwarz, MJ (2010). "Inflammatory Biomarkers and Depression". Neurotox. Res. 19 (2): 308–318. doi:10.1007/s12640-010-9210-2. PMID 20658274. S2CID 3225744.
  20. ^ Wonodi I, Colin-Stine O, Sathyasaikumar KV, et al. (2011). "Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes". Arch Gen Psychiatry. 68 (7): 665–674. doi:10.1001/archgenpsychiatry.2011.71. PMC 3855543. PMID 21727251.
  21. ^ Holtze M, Saetre P, Engberg G, et al. (2012). "Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls". J Psychiatry Neurosci. 37 (1): 53–57. doi:10.1503/jpn.100175. PMC 3244499. PMID 21693093.
  22. ^ Campbell, Brian M.; Charych, Erik; Lee, Anna W.; Möller, Thomas (2014). "Kynurenines in CNS disease: regulation byinflammatory cytokines". Frontiers in Neuroscience. 8 (12): 12. doi:10.3389/fnins.2014.00012. PMC 3915289. PMID 24567701.
  23. ^ Hoekstra, PJ; Anderson, GM; Troost, PW (2007). "Plasma kynurenine and related measures in tic disorder patients". Eur Child Adolesc Psychiatry. 16 (Suppl 1): 71–77. doi:10.1007/s00787-007-1009-1. PMID 17665285. S2CID 39150343.
  24. ^ Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, et al. (2014). "Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity". PLOS ONE. 9 (5): e97249. Bibcode:2014PLoSO...997249B. doi:10.1371/journal.pone.0097249. PMC 4023975. PMID 24836604.
  25. ^ Yukiko, Hirata; Takashi, Kawachi; Takashi, Sugimura (2 October 1967). "Fatty liver induced by injection of L-tryptophan". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 144 (2): 233–241. doi:10.1016/0005-2760(67)90153-1. PMID 4168935.
  • Foucher AL, McIntosh A, Douce G, Wastling J, Tait A, Turner CM (2006). "A proteomic analysis of arsenical drug resistance in Trypanosoma brucei". Proteomics. 6 (9): 2726–2732. doi:10.1002/pmic.200500419. PMID 16526094. S2CID 24074942.
  • Okamoto H, Hayaishi O (1967). "Flavin adenine dinucleotide requirement for kynurenine hydroxylase of rat liver mitochondria". Biochem. Biophys. Res. Commun. 29 (3): 394–399. doi:10.1016/0006-291X(67)90469-X. PMID 6076241.
  • Saito Y, Hayaishi O, Rothberg S (1957). "Studies on oxygenases; enzymatic formation of 3-hydroxy-L-kynurenine from L-kynurenine". J. Biol. Chem. 229 (2): 921–934. doi:10.1016/S0021-9258(19)63696-3. PMID 13502353.

March 08, 2024
kynurenine, monooxygenase, enzymology, kynurenine, monooxygenase, enzyme, that, catalyzes, chemical, reactionkynurenine, monooxygenasestructure, kynurenine, monooxygenase, dimer, generated, from, 4j34, monomer, depicted, cartoon, format, cyan, second, monomer,. In enzymology a kynurenine 3 monooxygenase EC 1 14 13 9 is an enzyme that catalyzes the chemical reactionkynurenine 3 monooxygenaseStructure of the kynurenine 3 monooxygenase dimer generated from 4J34 1 One monomer is depicted in cartoon format cyan and the second monomer is displayed in ribbon format green The flexible linker regions residues 96 104 are colored red Flavin adenine dinucleotide FAD is shown as spheres color coded according to atom type IdentifiersEC no 1 14 13 9CAS no 9029 61 2DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteins L kynurenine NADPH H O2 3 hydroxy L kynurenine NADP H2OKynurenine 3 monooxygenase is the expression product of the KMO gene The systematic name of this enzyme class is L kynurenine NADPH oxygen oxidoreductase 3 hydroxylating Other names in common use include kynurenine 3 hydroxylase kynurenine hydroxylase and L kynurenine 3 hydroxylase It participates in tryptophan metabolism through the kynurenine catabolic pathway This enzyme belongs to the family of oxidoreductases to be specific those acting on paired donors with O2 as the oxidant Kynurenine 3 monooxygenase catalyzes the insertion of molecular oxygen into the aromatic ring of kynurenine to produce 3 hydroxy L kynurenine 2 It employs one cofactor FAD Kynurenine 3 monooxygenase serves as an important branch point in the kynurenine pathway and as a result is an attractive drug target for immunological neurodegenerative and neuroinflammatory diseases 3 Currently most research on the kynurenine 3 monooxygenase enzyme has been focused primarily on rat models 4 and in yeast 5 both of which have been demonstrated to have high sequence homology with the human kynurenine 3 monooxygenase protein Studies have shown the beneficial effects of enzyme inhibition in these eukaryotic kynurenine 3 monooxygenase active sites thus making this enzyme an attractive target for human drug design 3 5 Contents 1 Structure 2 Active site 3 Mechanism 4 Biological function 5 Disease relevance 6 ReferencesStructure editKynurenine 3 monooxygenase is a dimer containing asymmetric subunits 5 and has one FAD binding domain as its prosthetic group 3 Kynurenine 3 monooxygenase contains a linker region involved in substrate binding following a second strand of an antiparallel b sheet a six stranded antiparallel b sheet domain and an a helix at the carboxy terminal 5 The hydrophobic C terminus acts as the mitochondrial anchoring domain and participates in enzymatic activity 6 Active site editWhile no scientific literature reports a crystal image of a kynurenine 3 monooxygenase complex with L kynurenine structural studies of the enzyme in yeast co crystallized with UPF 648 reveal how the FAD cofactor and substrate are bound in the active site 1 Chemical similarities between UPF 648 and L kynurenine suggest that the substrate binds adjacent to the Re face of the flavoprotein A loop containing the residues Pro321 Gln325 is believed to be the oxygen binding site above the re side of the FAD prosthetic group 5 Each monomer contains a conserved hydrophobic pocket residues Leu221 Met230 Ile232 Leu234 Phe246 Pro321 Phe322 positioned around the substrate s aromatic benzene moiety 5 A conserved Gln325 polar residue is also involved in hydrogen bonding on the L kynurenine carbonyl group as well as on the hydrogen on the FAD N3 atom 1 Arg83 and Tyr97 also form polar contacts with the carboxylate in the amino acid moiety on the substrate 7 Mechanism editKynurenine 3 monooxygenase catalyzes the hydroxylation of L kynurenine to 3 hydroxy L kynurenine with concomitant interconversion of NADPH to NADP The reaction mechanism is not entirely known but is believed to follow mechanisms related to the flavin dependent monooxygenases 8 After L kynurenine binds NADPH reduces FAD and leaves as NADP Oxygen then binds and creates an L kynurenine FAD hydroperoxide intermediate 5 9 This intermediate is the electrophilic source for the hydroxylation reaction yielding a primary ketimine form of the product and the C4a hydroxy FAD 10 Tautomerization yields 3 hydroxy L kynurenine in complex with the enzyme E Fl HOH P Dissociation of 3 hydroxy L kynurenine and H2O leads to the free enzyme E Flox nbsp The mechanism of kynurenine 3 monooxygenase 5 9 10 FAD is shown in blue The substrate intermediate and product are depicted in black Biological function editKynurenine 3 monooxygenase catalyzes the conversion of L kynurenine to 3 hydroxy L kynurenine an important bioactive metabolite in the kynurenine pathway The kynurenine pathway is responsible for over 95 of tryptophan oxidative degradation 11 L Kynurenine is an important branch point of this metabolic pathway being converted into the neurotoxin 3 hydroxy L kynurenine via kynurenine 3 monooxygenase the neuroprotectant kynurenic acid through kynurenine amino transferases or anthranilic acid by kynureninase 12 Kynurenine 3 monooxygenase regulates the downstream production of quinolinic acid which can generate reactive free radicals 13 and activates the NMDA subtype of glutamate receptors producing excitotoxic lesions in the central nervous system of mammals 14 15 Quinolinic acid is also the bioprecursor of NAD 12 Inhibition of kynurenine 3 monooxygenase leads to an increase of kynurenic acid in the kynurenine pathway This metabolite functions as an antagonist of the a7 nicotinic acetylcholine receptor and as an antagonist at the glycine site of the NMDA receptor 16 As a result regulation at the kynurenine 3 monooxygenase enzyme determines the neurotoxic and neuroprotective potential of the kynurenine pathway Disease relevance editKynurenine 3 monooxygenase is an attractive drug target for several neurodegenerative and neuroinflammatory diseases especially Huntington s Alzheimer s and Parkinson s disease Administration of potent enzyme inhibitors has demonstrated promising pharmacological results 3 5 Specifically genetic elimination of the kynurenine 3 monooxygenase enzyme has been shown to suppress toxicity of the huntingtin protein in yeast 17 and Drosophila 18 models of Huntington s disease Kynurenine 3 monooxygenase deficiency which can be caused by genetic polymorphisms cytokines or both 19 leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenic acid and anthranilic acid Recent research suggests that hyperphysiologic concentrations of kynurenine in kynurenine 3 monooxygenase deficient patients results in a shift towards kynurenic acid production believed to be related to cognitive deficits in predictive pursuit and visuospatial working memory 20 Kynurenine 3 monooxygenase deficiency is associated with disorders of the brain e g schizophrenia tic disorders and of the liver 21 22 23 24 25 References edit a b c Amaral M 2014 Crystal Structure of kynurenine 3 monooxygenase truncated at position 394 plus HIS tag cleaved doi 10 2210 pdb4j34 pdb a href Template Cite journal html title Template Cite journal cite journal a Cite journal requires journal help Filippini Graziella Allegri Costa Carlo V L Bertazzo Antonella International Meeting on Tryptophan Research 1998 Recent advances in tryptophan research tryptophan and serotonin pathways Advances in Experimental Medicine and Biology Vol 398 doi 10 1007 978 1 4613 0381 7 ISBN 978 1 4613 8026 9 S2CID 38080353 a b c d Smith Jason R Jamie Joanne F Guillemin Gilles J February 2016 Kynurenine 3 monooxygenase a review of structure mechanism and inhibitors Drug Discovery Today 21 2 315 324 doi 10 1016 j drudis 2015 11 001 ISSN 1359 6446 PMID 26589832 Horn U Ullrich V Staudinger H J 1971 Purification and characterization of L kynurenine 3 hydroxylase EC 1 14 1 2 from rat liver Hoppe Seyler s Z Physiol Chem 352 6 837 842 doi 10 1515 bchm2 1971 352 1 837 PMID 5087636 a b c d e f g h i Amaral M Levy C Heyes DJ Lafite P Outeiro TF Giorgini F Leys D Scrutton NS 2013 Structural basis of kynurenine 3 monooxygenase inhibition Nature 496 7445 382 385 Bibcode 2013Natur 496 382A doi 10 1038 nature12039 PMC 3736096 PMID 23575632 Hirai KH et al 2010 Dual role of the carboxyl terminal region of pig liver L kynurenine 3 monooxygenase mitochondrial targeting signal and enzymatic activity J Biochem 148 6 639 650 doi 10 1093 jb mvq099 PMID 20802227 Mole D et al 2016 Kynurenine 3 monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis Nature Medicine 22 2 202 209 doi 10 1038 nm 4020 PMC 4871268 PMID 26752518 Breton J et al 2000 Functional characterization and mechanism of action of recombinant human kynurenine 3 hydroxylase Eur J Biochem 267 4 1092 1099 doi 10 1046 j 1432 1327 2000 01104 x PMID 10672018 a b Crozier Reabe KR et al 2008 Kynurenine 3 monooxygenase from Pseudomonas fluorescens substrate like inhibitors both stimulate flavin reduction and stabilize the flavin peroxo intermediate yet result in the production of hydrogen peroxide Biochemistry 47 47 12420 12433 doi 10 1021 bi8010434 PMID 18954092 a b Entsch B et al 1976 Flavin oxygen derivatives involved in the hydroxylation of p hydroxybenzoate hydroxylase J Biol Chem 251 9 2550 2563 doi 10 1016 S0021 9258 17 33523 8 PMID 816794 Thevandavakkam MA et al 2010 Targeting kynurenine 3 monooxygenase KMO Implications for therapy in Huntington s disease CNS Neurol Disord Drug Targets 9 6 791 800 doi 10 2174 187152710793237430 PMID 20942784 a b Giorgini F Huang SY Sathyasaikumar KV et al 2013 Targeted Deletion of Kynurenine 3 Monooxygenase in Mice A New Tool for Studying Kynurenine Pathway Metabolism in Periphery and Brain The Journal of Biological Chemistry 288 51 36554 36566 doi 10 1074 jbc M113 503813 PMC 3868768 PMID 24189070 Rios C Santamaria A 1991 Quinolinic acid is a potent lipid peroxidant in rat brain homogenates Neurochem Res 16 10 1139 1143 doi 10 1007 bf00966592 PMID 1686636 S2CID 28669340 Stone T W Perkins M N 1981 Quinolinic acid A potent endogenous excitant at amino acid receptors in CNS Eur J Pharmacol 72 4 411 412 doi 10 1016 0014 2999 81 90587 2 PMID 6268428 Schwarcz R Bruno J P Muchowski P J Wu H Q 2012 Kynurenines in the mammalian brain When physiology meets pathology Nat Rev Neurosci 13 7 465 477 doi 10 1038 nrn3257 PMC 3681811 PMID 22678511 Hilmas C Pereira E F Alkondon M Rassoulpour A Schwarcz R Albuquerque E X 2001 The brain metabolite kynurenic acid inhibits a7 nicotinic receptor activity and increases non a7 nicotinic receptor expression Physiopathological implications J Neurosci 21 19 7463 7473 doi 10 1523 JNEUROSCI 21 19 07463 2001 PMC 6762893 PMID 11567036 Giorgini F Guidetti P Nguyen Q Bennett S C Muchowski P J 2005 A genomic screen in yeast implicates kynurenine 3 monooxygenase as a therapeutic target for Huntington disease Nat Genet 37 5 526 531 doi 10 1038 ng1542 PMC 1449881 PMID 15806102 Campesan S Green E W Breda C Sathyasaikumar K V Muchowski P J Schwarcz R Kyriacou C P Giorgini F 2011 The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington s disease Curr Biol 21 11 961 966 doi 10 1016 j cub 2011 04 028 PMC 3929356 PMID 21636279 Muller N Myint AM Schwarz MJ 2010 Inflammatory Biomarkers and Depression Neurotox Res 19 2 308 318 doi 10 1007 s12640 010 9210 2 PMID 20658274 S2CID 3225744 Wonodi I Colin Stine O Sathyasaikumar KV et al 2011 Downregulated Kynurenine 3 Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes Arch Gen Psychiatry 68 7 665 674 doi 10 1001 archgenpsychiatry 2011 71 PMC 3855543 PMID 21727251 Holtze M Saetre P Engberg G et al 2012 Kynurenine 3 monooxygenase polymorphisms relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls J Psychiatry Neurosci 37 1 53 57 doi 10 1503 jpn 100175 PMC 3244499 PMID 21693093 Campbell Brian M Charych Erik Lee Anna W Moller Thomas 2014 Kynurenines in CNS disease regulation byinflammatory cytokines Frontiers in Neuroscience 8 12 12 doi 10 3389 fnins 2014 00012 PMC 3915289 PMID 24567701 Hoekstra PJ Anderson GM Troost PW 2007 Plasma kynurenine and related measures in tic disorder patients Eur Child Adolesc Psychiatry 16 Suppl 1 71 77 doi 10 1007 s00787 007 1009 1 PMID 17665285 S2CID 39150343 Buness A Roth A Herrmann A Schmitz O Kamp H et al 2014 Identification of Metabolites Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity PLOS ONE 9 5 e97249 Bibcode 2014PLoSO 997249B doi 10 1371 journal pone 0097249 PMC 4023975 PMID 24836604 Yukiko Hirata Takashi Kawachi Takashi Sugimura 2 October 1967 Fatty liver induced by injection of L tryptophan Biochimica et Biophysica Acta BBA Lipids and Lipid Metabolism 144 2 233 241 doi 10 1016 0005 2760 67 90153 1 PMID 4168935 Foucher AL McIntosh A Douce G Wastling J Tait A Turner CM 2006 A proteomic analysis of arsenical drug resistance in Trypanosoma brucei Proteomics 6 9 2726 2732 doi 10 1002 pmic 200500419 PMID 16526094 S2CID 24074942 Okamoto H Hayaishi O 1967 Flavin adenine dinucleotide requirement for kynurenine hydroxylase of rat liver mitochondria Biochem Biophys Res Commun 29 3 394 399 doi 10 1016 0006 291X 67 90469 X PMID 6076241 Saito Y Hayaishi O Rothberg S 1957 Studies on oxygenases enzymatic formation of 3 hydroxy L kynurenine from L kynurenine J Biol Chem 229 2 921 934 doi 10 1016 S0021 9258 19 63696 3 PMID 13502353 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Kynurenine 3 monooxygenase amp oldid 1173537925, wikipedia, wiki, book, books, library,

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