Kynurenine 3-monooxygenase

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kynurenine 3-monooxygenase
Kynurenine 3-monooxygenase structure.png
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.
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EC no. 1.14.13.9
CAS no. 9029-61-2
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In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

Contents

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

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

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

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 FAD is shown in blue. The substrate, intermediate, and product are depicted in black. KMO Reaction Mechanism.pdf
The mechanism of kynurenine 3-monooxygenase FAD is shown in blue. The substrate, intermediate, and product are depicted in black.

Biological function

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

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]

Related Research Articles

<span class="mw-page-title-main">Flavin adenine dinucleotide</span> Redox-active coenzyme

In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.

<span class="mw-page-title-main">Kynureninase</span>

Kynureninase or L-Kynurenine hydrolase (KYNU) is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3-hydroxykynurenine and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2.

<span class="mw-page-title-main">Kynurenine</span> Chemical compound

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

<span class="mw-page-title-main">Kynurenic acid</span> Chemical compound

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<span class="mw-page-title-main">Squalene monooxygenase</span> Mammalian protein found in Homo sapiens

Squalene monooxygenase is a eukaryotic enzyme that uses NADPH and diatomic oxygen to oxidize squalene to 2,3-oxidosqualene. Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE gene. Several eukaryote genomes lack a squalene monooxygenase encoding gene, but instead encode an alternative squalene epoxidase that performs the same task.

<span class="mw-page-title-main">4-hydroxybenzoate 3-monooxygenase</span> Flavoprotein

The enzyme 4-hydroxybenzoate 3-monooxygenase, also commonly referred to as para-hydroxybenzoate hydroxylase (PHBH), is a flavoprotein belonging to the family of oxidoreductases. Specifically, it is a hydroxylase, and is one of the most studied enzymes and catalyzes reactions involved in soil detoxification, metabolism, and other biosynthetic processes.

<span class="mw-page-title-main">4-Hydroxyphenylacetate 3-monooxygenase</span> Class of enzymes

4-hydroxyphenylacetate 3-monooxygenase (EC 1.14.14.9) is an enzyme that catalyzes the chemical reaction

In enzymology, a salicylate 1-monooxygenase (EC 1.14.13.1) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Monooxygenase</span>

Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of NAD(P)H. One important subset of the monooxygenases, the cytochrome P450 omega hydroxylases, is used by cells to metabolize arachidonic acid (i.e. eicosatetraenoic acid) to the cell signaling molecules, 20-hydroxyeicosatetraenoic acid or to reduce or totally inactivate the activate signaling molecules for example by hydroxylating leukotriene B4 to 20-hydroxy-leukotriene B5, 5-hydroxyeicosatetraenoic acid to 5,20-dihydroxyeicosatetraenoic acid, 5-oxo-eicosatetraenoic acid to 5-oxo-20-hydroxyeicosatetraenoic acid, 12-hydroxyeicosatetraenoic acid to 12,20-dihydroxyeicosatetraenoic acid, and epoxyeicosatrienoic acids to 20-hydroxy-epoxyeicosatrienoic acids.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

<span class="mw-page-title-main">TPH1</span> Protein-coding gene in the species Homo sapiens

Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the TPH1 gene.

<span class="mw-page-title-main">KMO (gene)</span> Protein-coding gene in the species Homo sapiens

Kynurenine 3-monooxygenase is an enzyme that in humans is encoded by the KMO gene.

<span class="mw-page-title-main">Hypertryptophanemia</span> Medical condition

Hypertryptophanemia is a rare autosomal recessive metabolic disorder that results in a massive buildup of the amino acid tryptophan in the blood, with associated symptoms and tryptophanuria.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

<span class="mw-page-title-main">Biopterin-dependent aromatic amino acid hydroxylase</span>

Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic amino acid hydroxylase enzymes which includes phenylalanine 4-hydroxylase, tyrosine 3-hydroxylase, and tryptophan 5-hydroxylase. These enzymes primarily hydroxylate the amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, respectively.

Tryptophan N-monooxygenase (EC 1.14.13.125, tryptophan N-hydroxylase, CYP79B1, CYP79B2, CYP79B3) is an enzyme with systematic name L-tryptophan,NADPH:oxygen oxidoreductase (N-hydroxylating). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Tryptophan 7-halogenase</span>

Tryptophan 7-halogenase (EC 1.14.19.9, PrnA, RebH) is an enzyme with systematic name L-tryptophan:FADH2 oxidoreductase (7-halogenating). This enzyme catalyses the following chemical reaction:

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

<span class="mw-page-title-main">L-ornithine N5 monooxygenase</span> Enzyme

L-ornithine N5 monooxygenase (EC 1.14.13.195 or EC 1.14.13.196) is an enzyme which catalyzes one of the following chemical reactions:

L-ornithine + NADPH + O2 N(5)-hydroxy-L-ornithine + NADP+ + H2O L-ornithine + NAD(P)H + O2 N(5)-hydroxy-L-ornithine + NAD(P)+ + H2O

References

  1. 1 2 3 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. 398. doi:10.1007/978-1-4613-0381-7. ISBN   978-1-4613-8026-9. S2CID   38080353.
  3. 1 2 3 4 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. 1 2 3 4 5 6 7 8 9 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. 1 2 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. 1 2 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. 1 2 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.
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