Disease relevance of kynurenine

• Increased activity of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, was indicated in the macaques with SAIDS by reduced serum L-tryptophan and elevated serum L-kynurenine concentrations [1].
• The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses [2].
• Elevated kynurenine levels have been found in humans in a number of diseases and after interferon treatment, and the enzyme is induced in rodents after administration of interferon inducers, or influenza virus [3].
• To determine if similar effects result from interleukin 2 (IL-2) administration, plasma tryptophan and urinary kynurenine and neopterin were measured in patients undergoing a phase 1 toxicity trial of recombinant IL-2 given by daily bolus or continuous i.v. administration for 7 days at doses of 1 x 10(5) to 1 x 10(7) units/m2/day [4].
• Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy [5].

Psychiatry related information on kynurenine

• Increased kynurenine pathway metabolism has been implicated in the etiology of AIDS dementia complex (ADC) [6].
• Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable [7].
• Kynurenine in blood plasma and DST in patients with endogenous anxiety and endogenous depression [8].
• BACKGROUND: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy [9].
• Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD) [10].

High impact information on kynurenine

• Among the most potent suppressors was Bna4 (kynurenine 3-monooxygenase), an enzyme in the kynurenine pathway of tryptophan degradation that has been linked directly to the pathophysiology of Huntington disease in humans by a mechanism that may involve reactive oxygen species [11].
• Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro [12].
• To determine if this demonstrated mobility could be utilized to genetically transform the mosquito, a modified mariner element marked with a wild-type allele of the Drosophila melanogaster cinnabar gene was microinjected into embryos of a kynurenine hydroxylase-deficient, white-eyed recipient strain [13].
• We demonstrate also that ATP significantly potentiates the up-regulation of IDO--a negative regulator of T lymphocyte proliferation--and kynurenine production initiated by interferon-gamma (IFN-gamma) in human DCs [14].
• As a mechanism possibly contributing to monocyte-mediated T-cell suppression, we investigated monocyte tryptophan catabolism by indoleamine 2,3-dioxygenase into kynurenine, which has been implicated in regulating T-cell responses [15].

Chemical compound and disease context of kynurenine

• Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome [16].
• KAT catalyses the transamination of kynurenine and 3-hydroxykynurenine to kynurenic acid and xanthurenic acid respectively, and the enzyme activity can be easily detected in E. coli cells [17].
• Pneumococcal meningitis causes accumulation of neurotoxic kynurenine metabolites in brain regions prone to injury [18].
• Kynurenine aminotransferase and glutamine transaminase K of Escherichia coli: identity with aspartate aminotransferase [17].
• Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of pterin synthesis [19].

Biological context of kynurenine

• Superimposed on this state, stimulation of these cells caused a striking, additional increase (10-fold) in kynurenine release, and they triggered marked apoptosis of autologous post-HSCT T cells [15].
• Identification was confirmed by synthesis of the kynurenine amino acid adducts and comparison of the chromatographic retention times and mass spectra of these authentic standards with those of corresponding adducts isolated from human lenses following acid hydrolysis [20].
• Substrate specificity analysis of this mosquito transaminase demonstrates that the enzyme is active with 3-HK, kynurenine, or alanine substrates [21].
• Using calf lens proteins as a model, covalent binding of kynurenine to lens proteins has been shown to proceed via side chain deamination in a manner analogous to that observed for the related UV filter, 3-hydroxykynurenine O-beta-D-glucoside [20].
• A missense mutation in kynurenine aminotransferase-1 in spontaneously hypertensive rats [22].

Anatomical context of kynurenine

• We conclude that the amplified kynurenine release by post-HSCT monocytes, particularly induced upon stimulation, may underlie their suppressor activity, which in turn may contribute to the depressed T-cell immune responses after HSCT [15].
• Recently, expression of indoleamine 2,3-dioxygenase (IDO), which is induced by interferon-gamma (IFN-gamma) and catalyzes the conversion from tryptophan to kynurenine, has been identified as a T-cell inhibitory effector pathway in professional antigen-presenting cells [23].
• Cerebrospinal fluid KYNA levels increased in proportion to both IDO activity and L-KYN accumulation, though kynurenine aminotransferase activity was unaffected [24].
• Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack [25].
• Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO [26].

Associations of kynurenine with other chemical compounds

• The slightly increased kynurenine release and substantial release of neopterin by unstimulated post-HSCT monocytes suggests that they were in a state of continuous activation [15].
• In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine [3].
• Our results demonstrated that in various tissues, N-formylkynurenine produced by the dioxygenase from tryptophan was rapidly hydrolyzed into kynurenine by a kynurenine formamidase, but it was not further metabolized [27].
• A mixture of aminoadipate aminotransferase and kynurenine aminotransferase activities obtained after hydroxylapatite chromatography was subjected to affinity chromatography [28].
• Furthermore, growth of C. psittaci GPIC in HeLa cells, cultured in tryptophan-free medium, could be rescued by the addition of anthranilate, kynurenine or indole [29].

Gene context of kynurenine

• Cloning and functional expression of a soluble form of kynurenine/alpha-aminoadipate aminotransferase from rat kidney [30].
• Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells [31].
• Macrophage exposure to norharmane, an IDO inhibitor, resulted in a decreased formation of not only the kynurenine metabolites but also NO [32].
• Kynurenine aminotransferase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilic acid dioxygenase appeared to be constitutively expressed in both cell lines [31].
• 3-Hydroxyanthranilic acid 3,4-dioxygenase (3HAO) is a non-heme ferrous extradiol dioxygenase in the kynurenine pathway from tryptophan [33].

Analytical, diagnostic and therapeutic context of kynurenine

• Compared with controls, all post-HSCT monocyte-containing cell cultures (total PBMCs, monocytes, and monocyte/T-cell cocultures), but not monocyte-depleted populations, secreted elevated amounts of kynurenine [15].
• The more extensive modification of the urinary protein appears to be correlated with uremia, a condition in which the catabolism of tryptophan via the kynurenine pathway is increased, and the consequent rise in the concentration of its derivatives is accompanied by the oxidative processes due to the hemodialysis treatment [34].
• Free radical reactions photosensitized by the human lens component, kynurenine: an EPR and spin trapping investigation [35].
• More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC [36].
• Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography [37].

References