Kynurenine-anthranilate pathway

However, a more recent study exists [33], also based on the use of isotopically labeled anthranilic acid, which demonstrated that the substance is unable to increase HA levels in the liver and in the urines, when administered to rats on the contrary, such an increase was observed when either kynurenine or HA were administered, suggesting that the pathway, operating in mammals, should be kynurenine - HK - HA, and not kynurenine - anthranilic acid - HA. In that study, it was also concluded that the preferred route of kynurenine further metabolism was through... 

In addition to the pathway just outlined, tryptophan can result from the transamination of indole-pyruvic acid, but it seems unlikely that this reaction makes any important contribution to the biosynthesis. A trypto-phan-kynurenine-anthranilate-indole-tryptophan cycle has also been proposed i.e. the reverse of the catabolic pathway described in Fig. 58. However this sequence of reactions is only traversed if an excess of tryptophan is present and its function appears to be purely degradative. 

The kynurenine pathway metabolites are kynurenine, kynurenic acid, xahthurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid. The more important are kynurenine (Kyn) and 3-hydroxykynurenine (30HKyn) (Fig 1). 

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. 

Alloxan-diabetic animals, in which the conversion of tryptophan to methylnicotinamide was greatly impaired, excreted increased amounts of methylnicotinamide when very large doses of tryptophan were given, indicating that the defect may be due to changes in the kynurenine pathway of tryptophan (M5). Moreover, diabetic rats excreted much more xanthurenic acid and less anthranilic and 3-hydroxyanthranilic acids than did nondiabetics, following large doses (200-400 mg) of tryptophan. 

Interest then moved to animals. Both isotopic and nutritional experiments showed that the pathway established in microorganisms applied equally to mammals. Thus hydroxyanthranilic acid was converted to nicotinic acid (9, 604), which it could replace as a growth factor (944), whereas there was no similar conversion of anthranilic acid (343). An outstanding series of isotopic experiments, especially by Heidelberger and co-workers, showed that the 8-carbon atom of the tryptophan side chain became the 8-carbon atom of the kynurenine side chain and that the side chain was lost in conversion of kynurenine to nicotinic acid (369, 371, 427). Moreover the carbon in the 3-position of the indole nucleus became the carboxyl carbon of nicotinic acid (370 this experiment proved conclusively the reality of the tryptophan-nicotinic acid conversion) and the indole nitrogen appeared with only slight dilution in kynurenine, kynurenic acid, and xanthurenic acid (759). All these relations are those to be expected for the pathway tryptophan —+ kynurenine —> hydroxykynurenine (or its phosphate) —> hydroxyanthranilic acid (or its phosphate) — nicotinic acid, illustrated in diagrams 17 and 18. 

Fujigaki, S., Saito, K., Takemura, M., Fujii, H., Wada, H., Noma, A., and Seish-ima, M., Species differences in L-tryptophan-kynurenine pathway metabolism Quantification of anthranilic acid and its related enzymes, Arch. Biochem. Biophys., 358, 329, 1998. 

Tryptophan is also metabolized along the kynurenine pathway en route to nicotinic acid following its initial oxidation by tryptophan pyrro-lase. Several metabolites along this pathway are electroactive and include w-formylkynurenine, kynurenine, kynurenic acid, anthranilic acid, 3-hy-droxykynurenine, and xanthurenic acid. 

Hydroxyanthranilic acid is formed on two independent pathways a) from anthranilic acid by means of a monooxygenation (C 2.6.5), a reaction occurring in microorganisms and plants and b) by cleavage of 3-hydroxy-L-kynurenine (D 21.5) in plants and animals. 

Kynurenine Metaholism. Kynurenine may be metabolized in five ways acetylation to iV -acetylkynurenine,i decarboxylation to kynuramine, oxidation to 3-hydroxykynurenine, cyclization to a quinoline derivative, and cleavage to yield anthranilic acid." The oxidation, cyclization, and cleavage reactions are components of major pathways of tryptophan metabolism. Ommochrome is composed of a series of heterocyclic condensed ring systems that have been shown to be derived from tryptophan via kynurenine. The individual steps in the enzymatic formation of the pigments have not separated. ... 

The outcome of the different lines of investigation is that a number of pathways of tryptophan metabolism have been established. In the vertebrate organism the two well-known pathways are the kynurenine-hydroxyanthranilic acid and the serotonin pathways. Studies with Pseudomonas bacteria led Stanier and Hayaishi (876) to propose two pathways for the dissimilation of the products of tryptophan metabolism starting at the level of kynurenine. One of these is through anthranilic acid and catechol, referred to as the aromatic pathway, and the other through kynurenic acid, named the quinoline pathway. 

Interest in hydroxykynuienine in relation to niacin formation was aroused when it was observed that it yielded nicotinic acid in a Neurospora mutant with a genetic block after kynurenine (298). The compound was first isolated from the larvae of several insects (299, 300). Its importance in the kyniuenine pathway in the mammal was established when it was shown that it was converted to nicotinic acid and could replace the latter as a growth factor (301, 302). No similar conversion of anthranilic acid took place (503). Subsequently it was found that hydroxykynurenine was a constituent of the urine and that its excretion was increased in pyridoxine-deficient animals (304). 

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