If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Amino Acids Degradation → Proteinogenic Amino Acids Degradation → L-tryptophan Degradation|
Expected Taxonomic Range: Mammalia
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 184.108.40.206. In mammalian brain and other peripheral tissues and cells the kynurenine pathway is initiated by indoleamine 2,3-dioxygenase EC 220.127.116.11. 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]).
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)
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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
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
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
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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
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
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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
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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
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