3- Hydroxykynurenine transaminase

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). 

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. 

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... 

Kynurenic acid and xanthurenic acid, side products of the reaction, are the products of the transamination of the a-amino group of kynurenine and 3-hydroxy-kynurenine to a-ketoglutaric acid in the presence of pyridoxal phosphate and an enzyme found in mammalian liver and kidney, kynurenine transaminase. The keto acid resulting from the transamination reaction condenses spontaneously. Liver homogenate also decarboxylates 3-hydroxykynurenine to yield 4,8-de-hydroxyquinoline. Kynurenase may catalyze the cleavage of the side chain of kynurenine or 8-hydroxy-kynurenine and lead to the formation of alanine and... 

Kynureninase (Figure 11.16) is a pyridoxal phosphate-dependent enzyme, and its activity falls markedly in vitamin deficiency, at least partly because it undergoes a slow mechanism-dependent inactivation that leaves catalytically inactive pyridoxamine phosphate at the active site of the enzyme. The enzyme can only be reactivated if there is an adequate supply of pyridoxal phosphate. This means that in vitamin deficiency there is a considerable accumulation of both hydroxykynurenine and kynurenine, sufficient to permit greater metabolic flux than usual through kynurenine transaminase, resulting in increased formation of kynurenic and xanthurenic acids. 

The enzyme is active on both L-kynurenine and L-3-hydroxykynurenine. The D-isomers are inert. It requires pyridoxal phosphate as a coenzyme. The most effective amino-group acceptor is a-ketoglutarate, but other a-keto acids can also function. o-Aminobenzoylpyruvic acid, the expected product of the action of kynurenine transaminase on kynurenine, has not... 

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