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. 

Formation of xanthurenic acid is a typical feature of vitamin Be deficiency. It is the substance which first drew attention to the possible relationship between pyridoxine and the enzymes connected with protein metabolism. The formation of xanthurenic acid, however, is catalyzed by an enzyme, kynurenine transaminase, which requires pyridoxal phosphate as coenzyme. The apparent discrepancy between these two facts will be explained below. 

Quite recently Weber and Wiss (W8) studied the influence of vitamin Be depletion on various pyridoxal phosphate enzymes and found that rat liver kynureninase is much more affected by vitamin Be deficiency than kynurenine transaminase. In fact liver kynureninase of rats on a Be-deficient diet fell to 17%, whereas kynurenine transaminase was about 58% of the original activity after the same period. The different behavior of these two enzymes offers a way of studying closely the mechanism of the increased excretion of xanthurenic acid in pyridoxine... 

M3. Mason, M., and CuUekson, E. H., Estrogen-enzyme interactions inhibition and protection of kynurenine transaminase by the sulfate esters of diethylstilbestrol, estradiol, and estrone. J. Biol. Chem. 235, 1312-1316 (1960). 

Kynurminase, Kynurenine Transaminase, and the Formation of Anthranilic, Kynurenic, Hydroxyanthranilic, and Xanthurenic Acids... 

The detailed mechanism of pyridoxal phosphate participation in the kynureninase and kynurenine transaminase reactions is considered in detail later. Of interest in this connection is the finding that other amino... 

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. 

Studies in vitro with rat kidney tissue preparations showed that estrogen sulfates inhibit kynurenine transaminase in a reversible fashion that can be relieved by dialysis (MIO, Mil). Competition of sulfate and phosphate esters of estrogens with PLP for the kynurenine transaminase apoenzyme has been demonstrated (S5). An estrogen effect on this enzyme in vivo was suggested by the finding of higher enzyme activity in the kidneys of adult male rats than in either females or estrogen-treated males (M9, Mil). This difference applied to renal kynurenine transaminase, two-thirds of which is in the soluble fraction and the... 

Ogasawara, N., Hagino, Y., and Kotake, Y., Kynurenine-transaminase, kynureninase and the increase of xanthurenic add excretion. /. Biochem. (Tokyo) 52, 162-166 (1962). 

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... 

Kynurenine Transaminase. Both kynurenine and 3-hydroxykynu-renine participate in reactions with two enzymes that use pyridoxal phosphate. One is a transaminase that presumably forms the a-keto derivative of kynurenine. This compound does not accumulate, however ... 

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. 

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. 

Kynurenine Transaminase. This enzyme has been studied in liver and kidney (346, 347), in Pseudomonas (348) and in Neurospora (349). 

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... 

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. 

Kynurenine transaminase of rat kidney is inactivated at a pH less than 7.0 in the presence of phosphate, but this is prevented by the coenzyme, pyridoxal phosphate. 

Jakoby, W. B., and Bonner, D. M., 1956, Kynurenine transaminase from Neurospora, /. Biol. Chem. 221 689. 

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