Tryptophan Kynurenine transaminase

Under normal conditions, the rate-limiting enzyme of the pathway is tryptophan dioxygenase (Section 8.3.2), and there is hide accumulation of intermediates. Kynurenine transaminase, the enzyme which catalyzes the transamination and ring closure of kynurenine to kynurenic acid, and of hydroxykynurenine to xanthurenic acid, has a high relative to the normal steady-state concentrations of its substrates in the liver. Kynureninase and kynurenine hydroxylase have lower values of K, so that there is normally litde accumuladon of kynurenine or hydroxykynurenine. 

Induction of extrahepatic mdoleamine dioxygenase (which catalyzes the same reaction as tryptophan dioxygenase, albeit by a different mechanism) by bacterial lipopolysaccharides and mterferon-y may result in the production of relatively large amounts of kynurenine and hydroxykynurenine in tissues that lack the enzymes for onward metabolism. Kidney has kynurenine transaminase activity, and therefore extrahepatic metabolism of tryptophan may result in significant excretion of kynurenic and xanthurenic acids, even when vitamin Bg nutrition is adequate. 

Estrogens may modify the activity of enzymes in the kynurenine pathway other than the rate-limiting enzyme tryptophan pyrrolase. Mason and co-workers (M9, M12) have presented in vitro and in vivo evidence that estrogens may effect binding of PLP to the apoenzyme of kynurenine transaminase. 

The activity of this mechanism depends upon the presence of pyri-doxine. Thus pyridoxine plays still another role in connection with the metabolism of tryptophan, in addition to being a part of the coenzyme of kynureninase and kynurenine transaminase. 

The oxidative pathway of tryptophan metabolism is shown in Figure 3. Kynureninase is a pyridoxal phosphate-dependent enzyme, and in deficiency its activity is lower than that of tryptophan dioxygenase, so that there is an accumulation of hydroxy-kynurenine and kynurenine, resulting in greater metabolic flux through kynurenine transaminase and increased formation of kynurenic and xanthurenic acids. Kynureninase is exquisitely sensitive to vitamin Bg deficiency because it undergoes a slow inactivation as a result of catalysing the half-reaction of transamination instead of its normal reaction. The resultant enzyme with pyridoxamine phosphate at the catalytic site is catalytically inactive and can only be reactivated if there is an adequate concentration of pyridoxal phosphate to displace the pyridoxamine phosphate. 

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). 

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. 

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... 

Xanthurenic acid was the first tryptophan metabolite found to be elevated in the urine of pyridoxine-deficient animals (L5). When vitamin Be is deficient, liver kynureninase (Fig. 1) which is located in the cytosol, becomes rapidly depleted of PLP. However, the transaminases that metabolize kynurenine and 3-hydroxykynurenine to kynurenic acid and xanthiuenic acid, respectively, are located in both kidney and liver and... 

But in assessing the state of vitamin B nutrition, it is often advantageous to quantitate the urinary excretion of as many tryptophan metabolites as possible (P7). For example, in severe deficiency, as occurs in tuberculosis patients treated with isoniazid, the activities of both 3-hydroxykynureninase and 3-hydroxykynurenine transaminase are apparently markedly reduced, such that xanthurenic acid excretion may be normal and excretion of kynurenine and 3-hydroxykynurenine markedly increased (B20, P7). 

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