Tryptophan Peroxidase-Oxidase Adaptation

Tryptophan is, however, not the only agent which can bring about an increase in tryptophan peroxidase-oxidase. A smaller effect can be produced by substances which initiate the stress reaction of the adrenal-pituitary system (478). High X-irradiation produces a similar effect in normal, but not in adrenalectomized, animals (869). Cortisone reverses the effect of adrenalectomy (868), and glucocorticoids (e.g., cortisone and hydrocortisone) can themselves cause an increase in the enzyme (484). How these changes are brought about is still obscure their elucidation 

Experiments with mutants of microorganisms and insects, which made it likely that hydroxykynurenine is an intermediate in tryptophan metabolism, have been described above. Further evidence for the occurrence of hydroxykynurenine in insect larvae has siirce been reported (575, 844, 845), and its relation to eye-pigments is discussed below. It is also formed in plants (932). Strong support for participation in mammalian metabolism was provided by its identification in mammalian urine (171, 176, 292, and cf. further discussion later). 

No enzyme system which will oxidize kynurenine to hydroxykyiiurenitie has yet been isolated in a cell-free state from any species, and there is some evidence that direct conversion may not normally occur, at least in mammals. Riboflavin was suggested to be concerned in hydroxykynurenine formation at a comparatively early stage (387), and this has been supported by nutritional experiments. 

Diagram 19. Relation of vitamins to tryptophan metabolism. Deficiencies of 

It has been shown by the author that examination of the products excreted after administration of tryptophan to vitamin-deficient animals can give valuable information on the function of that vitamin in tryptophan metabolism (142, 171, 173). When tryptophan is given to the riboflavin-deficient rat there is a large excretion of those substances which lie to the left of line BB in diagram 19 (142, 582). This clearly indicates that this is the step at which riboflavin functions, and this is strongly supported by the fact that riboflavin deficiency can reduce up to ten-fold the conversion of tryptophan to quinolinic acid, whereas similar conversion of hydroxykynurenine is unaffected (385). On the other hand, the excretory pattern 

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Hydroxykynurenine excretion in pathological states was also first reported by Japanese workers (573), who identified it as the substance causing the diazo reaction and the Weiss urochromogen reaction in urines from cases of severe tuberculosis. This was confirmed in the author s laboratory (178), where it was also shown that the excretion is unrelated to tuberculosis as such. Hydroxykynurenine excretion occurs in a large proportion of patients with fevers of varying etiology and is in all probability due to the increased rate of breakdown of body proteins in fever. Presumably the protein breakdown induces an adaptive increase in tryptophan peroxidase-oxidase, and the capacity of the available kynureninase, which comes later in the metabolic chain and is not an adaptive enzyme (480), is exceeded. 

Hydroxytryptophan was not metabolized by a tryptophan-adapted strain of Pseudomonas (217) and was not attacked by the tryptophan peroxidase-oxidase system (217, 884). The enteramine and kynurenine pathways are quite distinct, as is supported by the facts that synthetic 5-hydroxykynurenine (124, 574), the expected product of tryptophan peroxidase-oxidase action, does not act as an ommochrome precursor in insects or as a nicotinic acid precursor in Neurospora (124). 

When synthesis of this compound was accomplished, > experiments with it made it clear that it is not a normal tryptophan metabolite. The metabolism of oxindolylalanine was found to be quite different from that of tryptophan or kynurenine in rat liver slices, or in the intact animal. The paper chromatographs of the urines from normal and pyridoxine-deficient rats fed oxindolylalanine were quite different from those obtained when tryptophan was fed. Furthermore, the tryptophan peroxidase-oxidase enzyme system does not act on this compound, nor was it metabolized by the bacillus. Pseudomonas fluorescens, which had been adapted to tryptophan or kynurenine. The identity of the first intermediate of tryptophan oxidation, therefore, is still unknown. 

The oxidative conversion of tryptophan to kynurenine was first observed in liver preparation by workers in the laboratory of Kotake (Itagaki and Nakayama, 1941). The low activity of the preparation described by Kotake was difficult to detect. Subsequently Knox and Mehler (1950) discovered the increased activity of livers from animals previously given large amounts of tryptophan. Liver served as the source of a slightly purified preparation that was described as tryptophan peroxidase-oxidase. A similar preparation was obtained from a Pseudomonas adapted to tryptophan (Hayaishi and Stanier, 1951). More recent evidence about the nature of the enzyme has forced the abandonment of the peroxidase-oxidase name and the original term suggested by Kotake, tryptophan pyrrolase, has been adopted as less descriptive but more correct. 

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