3-hydroxy-kynurenine

Fig.l. The more important metabolites of tryptorhan Degradation of the tryptophan accompanied with increasing in 10 times of kynurenine level in the case of renal failure. As the result of 3-hydroxy-kynurenine s ability of easy oxidize neurotoxin compounds form. 

Figure 9-53 Determination of lymphocyte kynureninase activity levels using HPLC. Enzyme activity is measured by quantification of formation of the product, 3-hydroxyanthranilic acid (3-HA A). (A) 3-HA A standard (12.0 nmol/L). (fl), Lymphocyte homogenate blank. (C) Lymphocyte 3-HAA production after 5 min of incubation in presence of 3-hydroxy-kynurenine. Peaks 1,3-HAA unmarked peaks are unidentified components. (From Ubbink et al., 1991.)...

Paper chromatographic analysis indicated that the abnormal excretion of xanthurenic acid always corresponded with higher amounts of other tryptophan metabolites such as kynurenine, acetylkynurenine, 3-hydroxy-kynurenine, and kynurenic and 3-hydroxyanthranilic acids after the usual load of tryptophan. 

Triplet detection. Time-resolved techniques (absorption spectroscopy or diffuse reflectance) allow for detection of the triplet state of the excited chromophore even in intact tissues. This technique has been used to determine the absence (Dillon and Atherton, 1990) of triplet formation by the endogenous 3-hydroxy-kynurenine, as well as the presence of triplets from sensitizing drugs in intact lenses (Roberts et al., 1991b). 

The crystal structure of kynureninase from P. fluorescens was solved in 2004. The enzyme shares the same structural fold as aspartate aminotransferase, but shares low sequence similarity. An active site arginine residue (Arg-375) was identified, which is important in substrate binding. The structure of the human kynureninase, which shows a catalytic preference for 3-hydroxy-kynurenine over L-kynurenine, was solved in 2007. The human enzyme shares the same fold as the P. fluorescens enzyme, and also contains an active site arginine residue (Arg-434). The catalytic mechanism requires two acid/base residues, which have not yet been unambiguously assigned. The hydrolytic cleavage step is believed to proceed via a general base mechanism. ... 

L-Kynurenine obtained from for the degradation of tryptophan is hydroxylated by a KMO homolog encoded by qbsG. The 3-hydroxy-kynurenine could be transam-inated into xanthurenic acid by the QbsB protein. The bifunctional protein QbsL activates xanthurenic acid via its N-terminal AMP (adenosine monophosphate) lig-ase domain, whereas the C-terminal domain of QbsL is responsible for the addition of the methyl group. QbsCDE proteins transfer sulfur from an unknown sulfur donor molecule. The participation and exact role of QbsK, a putative oxidoreductase, was not clear. Quinolobactin was proposed to result from the spontaneous hydrolysis of 8-hydroxy-4-methoxy-2-quinoline thiocarboxylic acid 17 [18]. 

Kynurenic acid and xanthurenic acid, side products of the reaction, are the products of the transamination of the a-amino group of kynurenine and 3-hydroxy-kynurenine to a-ketoglutaric acid in the presence of pyridoxal phosphate and an enzyme found in mammalian liver and kidney, kynurenine transaminase. The keto acid resulting from the transamination reaction condenses spontaneously. Liver homogenate also decarboxylates 3-hydroxykynurenine to yield 4,8-de-hydroxyquinoline. Kynurenase may catalyze the cleavage of the side chain of kynurenine or 8-hydroxy-kynurenine and lead to the formation of alanine and... 

It has been observed that the metabolism of tryptophan is also greatly influenced by riboflavin deficiency. In this deficiency there is an increased excretion of metabolic products of tryptophan such as N -acetylkynurenine, N -acetyl-3-hydroxy-kynurenine, kynurenic acid, and xanthurenic acid. In a search for the specific metabolic defect Charconnet-Harding, Dalgliesh, and Neuberger Biochem. J. London) 63, 513, 1953) concluded that riboflavin might be concerned with an unknown phosphorylation step but is not concerned with the oxidative hydroxyl-ation of kynurenine to hydroxykynurenine or anthranilic acid to hydroxyanthranilic acid. The authors also point out that riboflavin may have no specific metabolic role in tryptophan metabolism. 

After the oxidation of tryptophan to kynurenine, the side chain can be cleaved to yield anthranilic acid, or if prior oxidation to 3-hydroxy-kynurenine takes place, the product is 3-hydroxyanthraniIic acid. Alternatively, probably after the removal of the a-amino group to form the a-keto acids corresponding to kynurenine and 3-hydroxykynurenine, ring closure of the side chain can occur to yield kynurenic and xanthurenic acids. These alternative reactions will be discussed in turn. 

Disorder Tryptophan (P) pmol/l Tryptophan (U) pmol/ 24 h Indoleace-tate (U) pmol/24 h Indolelac-tate (U) pmol/24 h Indolepy-ruvate (U) pmol/24 h 5-Hydroxy-indoleace-tate (U) pmol/24 h 3-Hydroxy- kynurenine (U) Hmol/24 h Xanthurenic add (U) pmoI/24 h Kynurenic acid (U) pmol/24 h 3 -Hydr oxyky nurenine sulfate, acetyl-3-hy-droxyky n ur enine, acety Iky nurenine, conjugated xanthurenic acid... 

In the course of the metabolic transformation of trsrptophan to 3-hydroxyanthranilic acid and xanthurenic acid (Fig. 4), 3-hydroxy-kynurenine is formed from kynurenine (182,538). An enzymic system which catalyzes this reaction has been observed in the livers of rats and cats (198). This 3-hydroxylase occms in mitochondria. It appears to be specific for L-kynurenine because n-kynurenine, A -acetyl-L-kynurenine, AT-acetyl-D-kynurenine, kynurenic acid, and anthranilic acid are not attacked. Only the 3-position of kynurenine is hydroxylated. 

Vitamin deficiency may produce seborrhea-like symptoms. In addition, tryptophan catabolism is disturbed kynurenine, 3-hydroxy-kynurenine, and xanthurenic acid appear in urine. Excess pyridoxine is oxidized to pyridoxinic acid (like pyridoxal, but with a carboxyl in place of the aldehyde group) and excreted. 

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