Kynurenine, from tryptophan

It was observed in viral hepatitis (B16) that the production of kynurenine from tryptophan is disturbed owing to a cellular deficit in en-... 

Formation of kynurenine from tryptophan was discovered in liver extracts by Kotake and Masayama 289). These authors proposed the name tryptophan pyrrolase for the enzyme. Knox and Mehler 290) subsequently showed that the formation of kynurenine consisted of two enzyme reactions, an initial oxidation to formylkynurenine followed by hydrolysis to kynurenine. Because the reaction was stimulated by HsO produced in situ it was assumed that there was an intermediate formation and utilization of peroxide in the oxidation. For this reason the enzyme was renamed tryptophan oxidase-peroxidase by Knox. Experiments with O showed that molecular O2 was incorporated into the reaction products 291). One mole of O2 per mole of tryptophan was contained in the formylkynurenine. When H20 was tested, very little 0 was utilized. This observation led Tanaka and Knox 292) to return to the use of the original name, tryptophan pyrrolase. 

Hayaishi, O., S. Rothberg, A. H. Metler, and Y. Saito Studies on Oxygenases. Enzymatic Formation of Kynurenine from Tryptophan. J. Biol. Chem. 229, 889-896 (1957). 

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). 

During the first half of the twentieth century, when 87,000 people died from pellagra in the United States, there was a two-fold excess of females over males. Reports of individual outbreaks of pellagra show a similar sex ratio. This may well be the result of inhibition of kynureninase, and impairment of the activity of kynurenine hydroxylase, by estrogen metabolites, and hence reduced synthesis of NAD from tryptophan (Bender and Totoe, 1984b). 

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). 

Ommochromes are acid dyes of red, yellow-brown, and purple color, practically insoluble in all neutral solvents. The biogenesis of ommochromes from tryptophan is influenced by inheritance factors which act at definite steps. Kynurenine is formed under the control of v+ genes, and from it 3-hydroxykynurenine is formed under control of cn+ genes. 

INDOLMYCIN (20) is formed from pyruvate, and two enzymes active in initial stages of Its biosynthesis have been studied. They are a transaminase and aC-methyltransferase. The hypothetical route to indolmycin is by indole pyruvate, 3-methyl-indolepyruvate, indolmycenic acid (reduced alpha oxo group) and finally indolmycin which probably takes its amidine group from an arginine molecule 79. The closely related [pyrrolo (1,4) benzodiazepines] 80>81,82 antitumor antibiotics, anthramycin, tomaymycin and sibiromycin are formed from tryptophan (via the kynurenine pathway ), tyrosine and methionine-derived methyl groups 80.si.sz. 

Tryptophan is an essential amino acid involved in synthesis of several important compounds. Nicotinic acid (amide), a vitamin required in the synthesis of NAD+ and NADP+, can be synthesized from tryptophan (Figure 17-24). About 60 mg of tryptophan can give rise to 1 mg of nicotinamide. The synthesis begins with conversion of tryptophan to N-formylkynurenine by tryptophan pyrrolase, an inducible iron-porphyrin enzyme of liver. N-Formylkynurenine is converted to kynurenine by removal of formate, which enters the one-carbon pool. Kynurenine is hydroxylated to 3-hydroxykynurenine, which is converted to 3-hydroxyanthranilate, catalyzed by kynureninase, a pyridoxal phosphate-dependent enzyme. 3-Hydroxyanthranilate is then converted by a series of reactions to nicotinamide ribotide, the immedi-... 

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... 

Other neuroactive and neurotoxic metabohtes of tryptophan are also reportedly increased in the brain with chronic hver failure. One such example is quinolinic acid (QUIN) synthesized from tryptophan via the kynurenine pathway. QUIN synthesis is particularly sensitive to increased availability of tryptophan. QUIN has been identified in both rodent and human brain extracts and cerebral cortical QUIN concentrations are elevated in rats following portacaval anastomosis (Moroni et al., 1986a). Eurthermore, QUIN concentrations are increased up to sevenfold in CSF and autopsied frontal cortex of cirrhotic patients who died in hepatic coma (Moroni et al., 1986b). 

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. ... 

Phenoxazines also include yellow-to-brown and brownish-red pigments found in invertebrate animals and some vertebrates, for example as shielding pigments of eyes. The most important pigments are ommochromes that arise from tryptophan via kynurenine and 3-hydroxykynurenine. An example is a yellow pigment xanthommatin (9-69) containing bound aspartic acid. 

This conversion has been found to be catalyzed by an enzyme isolated from the liver and kidney of several mammalian species (6Jir67), from tryptophan-adapted Pseudomonas (68, 69), and from Neurospora (60). The enzyme appears to be identical with the system which causes the hydrolysis of 3-kynurenine to anthranilic acid. The products of the hydrolysis of hydroxykynurenine are hydroxyanthranilic acid and alanine. Pyri-doxal phosphate is required for the reaction. 

In the above-mentioned insect mutants, a chain of syntheses which forms the brown pigment of the eyes was interrupted the insects became conspicuous because of their light eyes. It was found that the pigment xanthommatin arises from tryptophan, and that in one group of mutants the step from tryptophan to ky-nurenine, and in another mutant the step from kynurenine to 3-hydroxykynuienine was blocked (Butenandt and co-workers) ... 

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). 

Figure 8.21 The formation of ommochromes and ommins from tryptophan via kynurenine...

Phenoxazines — The two main types of phenoxazines are the ommochromes and the microbial phenoxazines. The biosynthesis of ommochromes occurs via the kynurenine pathway. The tryptophan amino acid is converted to formylkynurenine and then to kynurenine and 3-hydroxykynurenine. Not all the steps of ommochrome synthesis are completely elucidated yet. Ommatins are dimers and ommins are oligomers of 3-hydroxykynurenine. - The papiliochromes are derived from tyrosine as well as from the tryptophan pathway. The key intermediate in the formation of papiliochromes is N-beta-alanyldopamine (NBAD). Papiliochromes are synthesized in special wing scale cells, before melanins. " "... 

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

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