Kynurenic acid formation

It was only many years after the discovery of tryptophan that a plausible degradative pathway could first be outlined, but during this early period a few tryptophan metabolites were identified. The long-known (559) kynurenic acid (structure, diagram 20 cf. 408) was shown in 1904 to be derived from tryptophan (220), but the considerable amount of work on kynurenic acid formation (reviewed by Neubauer, 637) gave few useful results. Neubauer (637), however, made the plausible (and correct) suggestion that it was derived from o-aminobenzoylpyruvic acid (structure, diagram 20). 

Hayaishi and Stanier found no evidence of kynurenic acid formation by bacterial kynureninase, either crude or purified. Analysis of the pathways of tryptophan metabolism by many different bacterial strains at first indicated that there was a sharp dichotomy of reaction sequence... 

Taniuchi H, O Hayaishi (1963) Studies on the metabolism of kynurenic acid. III. Enzymatic formation of 7,8-dihydroxykynurenic acid from kynurenic acid. J Biol Chem 238 283-293. 

Returning to the major tryptophan catabolic pathway, marked by green arrows in Fig. 25-11, formate is removed hydrolytically (step c) from the product of tryptophan dioxygenase action to form kynurenine, a compound that is acted upon by a number of enzymes. Kynureninase (Eq. 14-35) cleaves the compound to anthranilate and alanine (step d), while transamination leads to the cyclic kynurenic acid (step e). Hie latter is dehydroxylated in an unusual reaction to quinaldic acid, a prominent urinary excretion product. 

Tryptophan catabolism is also associated with several dead-end pathways, for example the formation of kynurenic and xanthurenic acids. Normal urine contains small amounts of hydroxykynurenine, kynurenine, kynurenic acid, and xanthurenic add. When large amounts of tryptophan are fed to animals, the excretion of these compounds increases. Xanthurenic acid is excreted in massive quantities in vitamin B6 deficiency. 

As discussed in Section 8.3.3, estrogen metabolites inhibit kynureninase and reduce the activity of kynurenine hydroxylase to such an extent that, even without induction of tryptophan dioxygenase (Section 9.5.4.1), the activity of these enzymes is lower than is needed for the rate of flux through the pathway, thus leading to increased formation of xanthurenic and kynurenic acids. 

SIN-1 (32) potently increased the extracellular concentration of kynurenic acid, an endogenous glutamate receptor antagonist, in cortical slices [49]. In contrast, it did not alter the activity of kynurenine aminotransferases (KAT I and II) and kynurenic acid biosynthetic enzymes. Thus, SIN-1 may play a neuroprotective role through the enhanced formation of kynurenic acid, which is a neuroinhibitory compound. 

Knox et al. (176) found that formation of anthranilic acid from kynurenine was always accompani by formation of kynurenic acid, and they considered that the keto acid (o-aminobenzoylpyruvic acid, diagram 20) might be a common intermediate in formation of both substances. This was soon disproved, and it is now clear that two independent reactions are involved, as illustrated in diagram 20. 

The increased plasma kynuremne pool and the induced xanthurenic acid urinary excretion have several implications in the assessment of diazinon noncholinergic toxicity. An increase in xanthurenic acid formation may alter glucose metabolism. Xanthurenic acid has been reported to form a complex with insulin and damage pancreatic P cells. Elevated plasma kynurenin may alter kynurenin transport into the brain. Since more than 40% of brain kynurenin originates from the systemic circulation, cerebral biosynthesis of neuroactive kynurenin metabolites such as quinolinic acid and kynurenic acid may change. Finally, the availability of L-iryptophan for other L-lryptophan-dependent processes may be reduced. Tryptophan is the metabolic precursor for. serotonin and nicotinic adenine dinucleotidc. Diabetes, bladder cancer, and neurological disorders may be the toxic consequences of diazinon-altered L-tryptophan metaboli.sm (Seifert and Pewnim, 1992 Pewnim and Seifert, 1993). 

Fic. 1. Metabolism of tryptophan to serotonin (5-hydroxytryptamine) and niacin. Fyiidoxal phosphate (PLP) dependent reactions are indicated. Reactions not shown which may result in formation of products excreted in urine include the acetylation of liymuenine and 3-hydroxykynurenine, conjugation of anthranilic acid with glycine (to form o-aminohippuric acid) and with glucuronic acid, and the dehydroxylation of kynurenic acid and xanthurenic add to quinaldic add and 8-hydroxyquinaldic add, respectively. 

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... 

Xanthurenic and kynurenic acids, and kynurenine and hydroxykynurenine, are easy to measure in urine, so the tryptophan load test (the ability to metabolize a test dose of 2—5 g of tryptophan) has been widely adopted as a convenient and very sensitive index of vitamin nutritional status. However, because glucocorticoid hormones increase tryptophan dioxygenase activity, abnormal results of the tryptophan load test must be regarded with caution, and cannot necessarily be interpreted as indicating vitamin B deficiency. Increased entry of tryptophan into the pathway will overwhelm the capacity of kynureninase, leading to increased formation of xanthurenic and kynurenic acids. Similarly, oestrogen metabolites inhibit kynureninase, leading to results that have been misinterpreted as vitamin B deficiency. 

The oxidation of tryptophan by various strains of Pseudomonas has been shown to proceed in all cases via kynurine. One sequence of reactions, the aromatic pathway, continues by eliminating the alanine side chain through the action of kynureninase, and subsequently utilizes oxygen for the formation of catechol and the pyrocatechase reaction already discussed. Another pathway retains the side chain of kynurenine and forms kynurenic acid through the action of kynurenine transaminase. A sequence of reactions has been indicated by recent work of Hayaishi and his associates (Kuno et al., 1961) this sequence appears to include three oxygenase reactions one hydroxylation and two phenolytic oxygenations (Fig. 18). 

Kynurminase, Kynurenine Transaminase, and the Formation of Anthranilic, Kynurenic, Hydroxyanthranilic, and Xanthurenic Acids... 

The increased excretion of kynurenic and xanthurenic acids observed in pyridoxine deficiency is probably due to the preferential combination of the pyridoxal phosphate coenzyme with the transaminase. By preventing the loss of the side chain, as a result of a decreased activity of kynureninase in pyridoxine deficiency, cyclization is favored leading to increased formation of the two acids above. 

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