Kynurenine from tryptophan metabolism

The disturbance of tryptophan metabolism in riboflavin deficiency, caused by impairment of kynurenine hydroxylase, can also result in reduced synthesis of NAD from tryptophan. This may therefore be a factor in the etiology of pellagra (Section 8.3.3.1). 

Studies with [ C] tryptophan in animals and isolated hepatocytes show that leucine does inhibit the synthesis of NAD from tryptophan, inhibiting metabolism at the level of kynurenine hydroxylase and kynureninase, causing the accumulation of intermediates. In isolated hepatocytes, the more... 

The second quinoline derivative produced in animal metabolism is xanthurenic acid, which was isolated by Musajo (M12). Xanthurenic acid (4,8-dihydroxyquinoline-2-carboxylic acid) also originates from tryptophan through kynurenine (M13). 

According to Zini (Zl), prolonged oral treatment with isonicotinic acid hydrazide interfered with tryptophan metabolism, probably by inhibiting kynureninase activity, which catalyzes the synthesis of anthra-nilic acid from kynurenine. 

In view of the current interest in hydroxylation reactions in vivo it is to be hoped that this stage of tryptophan metabolism will receive more detailed attention from enzymologists. At present it can be stated definitely only that kynurenine (or possibly a derivative such as A -acetylkynurenine 170, 173) is converted either to hydroxykynurenine or to some simple derivative at the same level of oxidation. It is of interest that both kynurenine and hydroxykynurenine are formed on photooxidation of tryptophan, especially in the presence of ferrous iron (972). 

W -Acetylkynurenine (i.e., acetylated on the aliphatic amino group) was isolated from a Neurospora mutant culture (970) and was also found in the urine of pyridoxine-deficient rats together with the analogous iV -acetylhy-droxykynurenine (171). It is possible, though there is no direct evidence, that these Af -acetyl derivatives play some part in normal tryptophan metabolism in the rat (c/. 170, 173), or they may, as is probably the case in Neurospora, merely be products of side reactions occurring in the presence of abnormal amounts of kynurenine and hydroxykynurenine. Hydroxykynurenine is also excreted by the pyridoxine-deficient rat as its 0-sulfate... 

Our knowledge of tryptophan began some 100 years ago. In 1901 Hopkins and Cole1 isolated tryptophan from a pancreatic digest of casein. Its structure was established in 1907 by Ellinger and Flamand,2 who synthesized a substance that was identical to the tryptophan isolated by Hopkins and Cole. It is noteworthy that about 50 years prior to the discovery of tryptophan by Hopkins and Cole,1 aspects of tryptophan metabolism began to appear in the research literature, when in 1853 Liebig discovered kynurenic acid in dog urine.3 Subsequently, kynurenine, a tryptophan metabolite, was identified,4 5 and the relationship of kynurenic acid to tryptophan was understood. A brief review on the discovery of tryptophan has been described by Curzon.6... 

From 1978 to 1985 renewed interest in tryptophan metabolism via the kynurenine-niacin pathway was generated by the findings of Hayaishi et al. and others of a second enzyme, namely, indoleamine-2,3-dioxygenase (IDO).2 3 This enzyme was found to be present in several nonhepatic tissues (lung, intestine, brain, and epididymis) and cells (blood monocytes, macrophages, and eosinophils). The enzyme normally has very low activity but is induced to very high activity by stimulation of immune systems with interferon-y1-8 or interleukin-2 (cytokines).9 Thus, inflammatory processes, infections, and immune stimulation that induce interferon-y could lead to... 

If the dietary levels of niacin and tryptophan are insufficient, the condition known as pellagra results. The symptoms of pellagra are dermatitis, diarrhea, dementia, and, finally, death. In addition, abnormal metabolism of tryptophan occurs in a vitamin B6 deficiency. Kynurenine intermediates in tryptophan degradation cannot be cleaved because kynureninase requires PLP derived from vitamin B6. Consequently, these intermediates enter a minor pathway for tryptophan metabolism that produces xanthurenic acid, which is excreted in the urine. 

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. ... 

Several alternative pathways of L-tryptophan metabolism diverge from kynurenine (24). In mammals the quantitatively major fate of the benzene ring of the amino acid appears to be its oxidation to carbon dioxide via 3-hydroxyanthranilic acid (25), Figure 4.5. Kynurenine is first hydroxylated by a typical mixed function oxidase and the side chain is then removed, under the... 

Initially, 3-hydroxykynurenine was not discovered as the intermediate for nicotinic acid formation but rather for ommochrome formation (Butenandt and co-workers). Ommochromes are pigments found chiefly among insects and crabs. The simplest representative, xarUhommaline (formula in Chapt. VII-6) easy to prepare in vitro by careful oxidation of hydroxykynurenine. The synthesis of ommochromes is disrupted in several mutants of the fruitfly Drosophila (and other insects) either the transition from tryptophan to kynurenine or its oxidation to hydroxykynurenine is blocked. The pigmentation of insect eyes was one of the first examples of the thesis that hereditary factors control biochemical reactions (cf. Chapt. VII-6). Other examples, even in man, are provided by the metabolism of tyrosine (cf. Chapt. VII-6). 

From our investigation it is evident that abnormal excretion of tryptophan metabolites is not a typical feature of bladder tumor subjects, since human beings with neoplastic and nonneoplastic extrabladder urinary diseases have also been found to excrete spontaneously elevated amounts of tryptophan derivatives. It seems that the metabolic abnormality is not restricted to bladder tumors, but is rather more specific for patients with tumors of the upper urinary tracts and of the renal parenchyma. Actually 59% of these patients (Fig. 4) excreted abnormal amounts of kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. 

Oka and Leppanen (03) also have suggested that the metabolism of tryptophan may be abnormal in rheumatoid arthritis. From chromatographic investigations of urinary indole excretion they concluded that, in such patients, there might be some alteration in the metabolism of the amino acid by the kynurenine pathway. 

Hydroxykynurenine excretion in fever is sometimes accompanied by smaller amounts of kynurenine, whereas if excess tryptophan is taken by mouth large amounts of kynurenine, but negligible hydroxykynurenine, are excreted. These differences in metabolism of exogenous and endogenous tryptophan are unlikely to be due to use of different metabolic pathways and suggest that tryptophan molecules from endogenous protein breakdown and from exogenous sources do not necessarily equilibrate in a common body tryptophan pool. ... 

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). 

Evidence (104,116) suggests that D-tryptophan is not fully utilized by human subjects and may have harmful effects. Further studies showed that D-tryptophan did not maintain nitrogen balance in normal young men (106), and in another study (117), urine from normal human subjects, after ingestion of D-tryptophan, contained a considerable portion of this compound as well as D-kynurenine. In contrast, the rat utilizes D-tryptophan completely however, food intake is significantly less in D-tryptophan-fed rats than in rats fed a diet containing L-tryptophan (110). The metabolic conversion of the D- to the L-enantiomer takes place in the rat liver and kidney D-amino acid oxidase plays a key role in this conversion (109). Indole pyruvic acid can be converted to L-tryptophan by a stereospecific transaminase apparently absent in humans The chick, on the other hand, utilizes only 7-40% of the D-tryptophan (82,83,110, 113). This wide range of values is probably due to different experimental conditions. D-tryptophan and... 

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