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MetaCyc Pathway: L-tryptophan degradation XI (mammalian, via kynurenine)
Inferred from experimentTraceable author statement to experimental support

Pathway diagram: L-tryptophan degradation XI (mammalian, via kynurenine)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Degradation/Utilization/AssimilationAmino Acids DegradationProteinogenic Amino Acids DegradationL-tryptophan Degradation

Some taxa known to possess this pathway include : Felis catus, Homo sapiens, Mus musculus, Rattus norvegicus

Expected Taxonomic Range: Mammalia

General Background

In mammals L-tryptophan is an essential amino acid that must be obtained in the diet. It is utilized in protein synthesis and in biosynthesis of the neurotransmitter serotonin. It is catabolized via the kynurenine pathway in most tissues. This pathway is the major catabolic route of L-tryptophan in mammals, as well as an anabolic source of NAD+. L-tryptophan is also catabolized via the serotonergic pathway in the central nervous system (CNS), producing serotonin and other indoleamines. Metabolites of the kynurenine pathway are involved in many biological processes. In the CNS products of both pathways have consequences for the modulation of physiology and behavior and for the pathophysiology of some diseases (in [Ball09], [Heyes97] and reviewed in [Ruddick06] and [Schwarcz04]). See pathways L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde and its pathway links and pathway serotonin and melatonin biosynthesis.

About This Pathway

The kynurenine pathway in mammalian liver is initiated by tryptophan 2,3-dioxygenase, EC In mammalian brain and other peripheral tissues and cells the kynurenine pathway is initiated by indoleamine 2,3-dioxygenase EC This is the first and rate-determining step of this pathway. In addition to the acidic metabolites shown in pathway L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde, other reactions can form the acidic, neuroactive metabolites kynurenate, anthranilate, xanthurenate and picolinate, as shown in this pathway.

L-kynurenine can be enzymatically converted to the neuroactive compounds kynurenate (via transamination) or anthranilate (via hydrolysis). 3-hydroxy-L-kynurenine can be enzymatically transaminated to xanthurenate, possibly by the same enzyme that transaminates L-kynurenine. aminocarboxymuconate semialdehyde is an unstable intermediate in the kynurenine pathway that is transformed spontaneously into quinolinate (see linked pathway NAD biosynthesis from 2-amino-3-carboxymuconate semialdehyde), or enzymatically into 2-aminomuconate 6-semialdehyde. 2-aminomuconate 6-semialdehyde can undergo spontaneous cyclization to picolinate, or enzymatic conversion to 2-aminomuconate. picolinate has been identified in body fluids, including cerebrospinal fluid (in [Coggan09, Heyes97, Batabyal07] and [Vamos09] and reviewed in [PerezDe07]).

In rat brain slices, evidence has been presented that 3-hydroxyanthranilate may be preferentially produced by microsomal hydroxylation of anthranilate by unspecified hydroxylases [Baran90]. However, mouse studies supported the formation of 3-hydroxyanthranilate from 3-hydroxy-L-kynurenine in brain and from hydroxylation of anthranilate in peripheral tissues [Chiarugi96, Cannazza03]. Therefore, this remains to be investigated in other species and tissues (in [Fujigaki98]).

As noted above, metabolites of the kynurenine pathway are involved in many biological processes. Some of these metabolites are potentially toxic if their levels are increased in various disorders. The physiological functions of kynurenate, anthranilate, xanthurenate and picolinate are under investigation (reviewed in [PerezDe07]). xanthurenate is a possible synaptic signaling molecule in brain [Gobaille08]. Although quinolinate is neurotoxic, kynurenate and picolinate are neuroprotective (in [Guillemin07]). anthranilate may be involved in oxidative stress and neuronal damage (reviewed in [Vamos09]).

Subpathways: 2-amino-3-carboxymuconate semialdehyde degradation to glutaryl-CoA, L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde, anthranilate degradation IV (aerobic)

Variants: L-tryptophan degradation I (via anthranilate), L-tryptophan degradation II (via pyruvate), L-tryptophan degradation III (eukaryotic), L-tryptophan degradation IV (via indole-3-lactate), L-tryptophan degradation V (side chain pathway), L-tryptophan degradation VI (via tryptamine), L-tryptophan degradation VII (via indole-3-pyruvate), L-tryptophan degradation VIII (to tryptophol), L-tryptophan degradation IX, L-tryptophan degradation X (mammalian, via tryptamine), L-tryptophan degradation XII (Geobacillus)

Created 30-Jul-2009 by Fulcher CA, SRI International


Ball09: Ball HJ, Yuasa HJ, Austin CJ, Weiser S, Hunt NH (2009). "Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway." Int J Biochem Cell Biol 41(3);467-71. PMID: 18282734

Baran90: Baran H, Schwarcz R (1990). "Presence of 3-hydroxyanthranilic acid in rat tissues and evidence for its production from anthranilic acid in the brain." J Neurochem 55(3);738-44. PMID: 2384749

Batabyal07: Batabyal D, Yeh SR (2007). "Human tryptophan dioxygenase: a comparison to indoleamine 2,3-dioxygenase." J Am Chem Soc 129(50);15690-701. PMID: 18027945

Cannazza03: Cannazza G, Baraldi M, Braghiroli D, Tait A, Parenti C (2003). "High-performance liquid chromatographic method for the quantification of anthranilic and 3-hydroxyanthranilic acid in rat brain dialysate." J Pharm Biomed Anal 32(2);287-93. PMID: 12763538

Chiarugi96: Chiarugi A, Carpenedo R, Moroni F (1996). "Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and of kynureninase." J Neurochem 67(2);692-8. PMID: 8764597

Coggan09: Coggan SE, Smythe GA, Bilgin A, Grant RS (2009). "Age and circadian influences on picolinic acid concentrations in human cerebrospinal fluid." J Neurochem 108(5);1220-5. PMID: 19141084

Fujigaki98: Fujigaki S, Saito K, Takemura M, Fujii H, Wada H, Noma A, Seishima M (1998). "Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes." Arch Biochem Biophys 358(2);329-35. PMID: 9784247

Gobaille08: Gobaille S, Kemmel V, Brumaru D, Dugave C, Aunis D, Maitre M (2008). "Xanthurenic acid distribution, transport, accumulation and release in the rat brain." J Neurochem 105(3);982-93. PMID: 18182052

Guillemin07: Guillemin GJ, Cullen KM, Lim CK, Smythe GA, Garner B, Kapoor V, Takikawa O, Brew BJ (2007). "Characterization of the kynurenine pathway in human neurons." J Neurosci 27(47);12884-92. PMID: 18032661

Heyes97: Heyes MP, Chen CY, Major EO, Saito K (1997). "Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types." Biochem J 326 ( Pt 2);351-6. PMID: 9291104

Okuno08: Okuno A, Fukuwatari T, Shibata K (2008). "Urinary excretory ratio of anthranilic acid/kynurenic acid as an index of the tolerable amount of tryptophan." Biosci Biotechnol Biochem 72(7);1667-72. PMID: 18603814

PerezDe07: Perez-De La Cruz V, Konigsberg M, Santamaria A (2007). "Kynurenine pathway and disease: an overview." CNS Neurol Disord Drug Targets 6(6);398-410. PMID: 18220779

Ruddick06: Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA (2006). "Tryptophan metabolism in the central nervous system: medical implications." Expert Rev Mol Med 8(20);1-27. PMID: 16942634

Schwarcz04: Schwarcz R (2004). "The kynurenine pathway of tryptophan degradation as a drug target." Curr Opin Pharmacol 4(1);12-7. PMID: 15018833

Vamos09: Vamos E, Pardutz A, Klivenyi P, Toldi J, Vecsei L (2009). "The role of kynurenines in disorders of the central nervous system: possibilities for neuroprotection." J Neurol Sci 283(1-2);21-7. PMID: 19268309

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

AlberatiGiani96: Alberati-Giani D, Buchli R, Malherbe P, Broger C, Lang G, Kohler C, Lahm HW, Cesura AM (1996). "Isolation and expression of a cDNA clone encoding human kynureninase." Eur J Biochem 239(2);460-8. PMID: 8706755

AlberatiGiani97: Alberati-Giani D, Cesura AM, Broger C, Warren WD, Rover S, Malherbe P (1997). "Cloning and functional expression of human kynurenine 3-monooxygenase." FEBS Lett 410(2-3);407-12. PMID: 9237672

Austin09: Austin CJ, Astelbauer F, Kosim-Satyaputra P, Ball HJ, Willows RD, Jamie JF, Hunt NH (2009). "Mouse and human indoleamine 2,3-dioxygenase display some distinct biochemical and structural properties." Amino Acids 36(1);99-106. PMID: 18274832

Basran08: Basran J, Rafice SA, Chauhan N, Efimov I, Cheesman MR, Ghamsari L, Raven EL (2008). "A kinetic, spectroscopic, and redox study of human tryptophan 2,3-dioxygenase." Biochemistry 47(16);4752-60. PMID: 18370401

Brady75: Brady FO (1975). "Tryptophan 2,3-dioxygenase: a review of the roles of the heme and copper cofactors in catalysis." Bioinorg Chem 5(2);167-82. PMID: 178384

Breton00: Breton J, Avanzi N, Magagnin S, Covini N, Magistrelli G, Cozzi L, Isacchi A (2000). "Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase." Eur J Biochem 267(4);1092-9. PMID: 10672018

Brown86: Brown D, Hitchcock MJ, Katz E (1986). "Purification and characterization of kynurenine formamidase activities from Streptomyces parvulus." Can J Microbiol 32(6);465-72. PMID: 2425918

Calderone02: Calderone V, Trabucco M, Menin V, Negro A, Zanotti G (2002). "Cloning of human 3-hydroxyanthranilic acid dioxygenase in Escherichia coli: characterisation of the purified enzyme and its in vitro inhibition by Zn2+." Biochim Biophys Acta 1596(2);283-92. PMID: 12007609

Christensen07: Christensen M, Duno M, Lund AM, Skovby F, Christensen E (2007). "Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase." J Inherit Metab Dis 30(2);248-55. PMID: 17334708

Colabroy05: Colabroy KL, Begley TP (2005). "Tryptophan catabolism: identification and characterization of a new degradative pathway." J Bacteriol 187(22);7866-9. PMID: 16267312

Comings95: Comings DE, Muhleman D, Dietz G, Sherman M, Forest GL (1995). "Sequence of human tryptophan 2,3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat." Genomics 29(2);390-6. PMID: 8666386

Dai90: Dai W, Gupta SL (1990). "Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA." Biochem Biophys Res Commun 168(1);1-8. PMID: 2109605

Danhauser12: Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E, Zschocke J, Strom TM, Traub T, Okun JG, Meitinger T, Hoffmann GF, Prokisch H, Kolker S (2012). "DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria." Am J Hum Genet 91(6);1082-7. PMID: 23141293

DAniello05a: D'Aniello A, Fisher G, Migliaccio N, Cammisa G, D'Aniello E, Spinelli P (2005). "Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients." Neurosci Lett 388(1);49-53. PMID: 16039064

Fuchs08: Fuchs G (2008). "Anaerobic metabolism of aromatic compounds." Ann N Y Acad Sci 1125;82-99. PMID: 18378589

Fukuoka02: Fukuoka S, Ishiguro K, Yanagihara K, Tanabe A, Egashira Y, Sanada H, Shibata K (2002). "Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and "quinolinate hypothesis"." J Biol Chem 277(38);35162-7. PMID: 12140278

Goh02: Goh DL, Patel A, Thomas GH, Salomons GS, Schor DS, Jakobs C, Geraghty MT (2002). "Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT)." Mol Genet Metab 76(3);172-80. PMID: 12126930

Guidetti07: Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R (2007). "Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain." J Neurochem 102(1);103-11. PMID: 17442055

Han01: Han Q, Fang J, Li J (2001). "Kynurenine aminotransferase and glutamine transaminase K of Escherichia coli: identity with aspartate aminotransferase." Biochem J 360(Pt 3);617-23. PMID: 11736651

Han04: Han Q, Li J (2004). "pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I." Eur J Biochem 271(23-24);4804-14. PMID: 15606768

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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