Kynureninase and

Actinomycin.—Kynurenine and 3-hydroxykynurenine are actinomycin precursors in Streptomyces antibioticus (cf. Vol. 6, p. 42). Recently, kynureninase and hydroxykynureninase activity has been identified in S. parvulus cultures and the latter activity was found to show correlation with actinomycin formation.57... 

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). 

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. 

As discussed in Section 8.3.3, estrogen metabolites inhibit kynureninase and reduce the activity of kynurenine hydroxylase to such an extent that, even without induction of tryptophan dioxygenase (Section 9.5.4.1), the activity of these enzymes is lower than is needed for the rate of flux through the pathway, thus leading to increased formation of xanthurenic and kynurenic acids. 

As discussed in Section 9.5.4.2, estrogen metabolites inhibit kynureninase, and they also lead to reduced activity of kynurenine hydroxylase. As a result, in pregnancy or in response to (high-dose) oral contraceptives, tissue concentrations of kynurenine, hydroxykynurenine, xanthurenic, and kynurenic acids are higher than normal. 

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... 

As discussed above, inhibition of key enzymes of the KP (Fig. 1) may represent a viable opportunity to develop therapeutic agents for the treatment of a number of inflammatory, neurodegenerative, and psychiatric disorders. In this section, we will review the available chemical inhibitors of the different enzymes in the KP, with a broader focus on KMO however, we will also briefly review the current status of inhibitors of IDO, kynurenine aminotransferase II (KAT II), kynureninase, and 3-hydroxyanthranilic acid oxygenase (HAO). 

Giordani A, Corti L, Cini M, Marconi M, Pillan A, Ferrario R, Schwarcz R, Guidetti P, Speciale C, Varasi M (1996) Benzoylalanine analogues as inhibitors of rat brain kynureninase and kynurenine 3-hydroxylase. Adv Exp Med Biol 398 499-505... 

M12. Mason, M., and Manning, B., Effects of steroid conjugates on availability of pyridoxal phosphate for kynureninase and kynurenine aminotransferase activity. Amer. J. Clin. Nutr. 24, 786-791 (1971). 

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

Troost T, Hitchcock, MJM, Katz E. Distinct kynureninase and hydroxykynuieniriase enzymes itv an actinomycin.producing strain of Scrapcomyces (kiiWus. Biochim Biophys Acta 1980 612 97-106,... 

Gaertner FH, Cole, KW, Welch, GR. Evidence for distinct kynureninase and hydroxy-kynuteninase activities in Neurosfwrti crossa. J Bactetiol 1971 108 902-909. 

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. 

Oral contraceptives do not cause vitamin deficiency. The problem is that oestrogen metabolites inhibit kynureninase and reduce the activity of kynurenine hydroxylase. This results in the excretion of abnormal amounts of tryptophan metabolites, similar to what is seen in vitamin B deficiency, but for quite a different reason. 

The ability to metabolise a test dose of tryptophan has been widely adopted as a convenient and sensitive index of vitamin Bg nutritional status. However, induction of tryptophan dioxygenase by glucocorticoid hormones will result in a greater rate of formation of kynurenine and hydroxykynurenine than the capacity of kynureninase, and will thus lead to increased formation of kynurenic and xanthurenic acids—an effect similar to that seen in vitamin Bg deficiency. Such results may be erroneously interpreted as indicating vitamin Bg deficiency in a variety of subjects whose problem is increased glucocorticoid secretion as a result of stress or illness, not vitamin Bg deficiency. 

A number of drugs that react with carbonyl compounds are capable of causing vitamin Bg deficiency on prolonged use. These include the antituberculosis drug isoniazid (iso-nicotinic acid hydrazide), penicillamine, and the anti-Parkinsonian drugs, benser-azide and carbidopa. In general, the main effect is impairment of tryptophan metabolism by inhibition of kynureninase, and hence the development of the niacin-deficiency disease, pellagra. The condition therefore responds to the administration of either vitamin Bg or niacin. 

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). 

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