Kynureninase action

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

Returning to the major tryptophan catabolic pathway, marked by green arrows in Fig. 25-11, formate is removed hydrolytically (step c) from the product of tryptophan dioxygenase action to form kynurenine, a compound that is acted upon by a number of enzymes. Kynureninase (Eq. 14-35) cleaves the compound to anthranilate and alanine (step d), while transamination leads to the cyclic kynurenic acid (step e). Hie latter is dehydroxylated in an unusual reaction to quinaldic acid, a prominent urinary excretion product. 

Cleavage of 3-hydroxykynurenine by kynureninase (step g, Fig. 25-11) forms 3-hydroxyanthranilate, which is opened under the action of another dioxygenase (step h) with eventual degradation to acetyl-CoA, as indicated. In insects the reactive 3-hydroxyanthranilate is utilized in "tanning" reactions, e.g., coupling to tyrosine residues to toughen insect cuticles and walls of cocoons.214... 

The third kind of hydroxylase activity is the only one pertinent to the present review and refers to a mono-oxygenase of the hydroxylase type. This catalyses the insertion of a -OH group in place of a hydrogen atom at the 3-position of anthranilic acid, leading to HA. This evenience is often simply ignored by many authors dealing with tryptophan metabolism, so it could seem that the only possibility of HA formation is the action of kynureninase on HK. The actual occurrence of a true hydroxylase, as defined above, could however be considered debatable for a number of reasons, but some authors merely notice the activity without giving any reference to it. 

More recently Wiss found that kynureninase inactivated by dialysis could be reactivated by pyridoxal-5-phosphate, but not by pyridoxal-2-phosphate. As pyridoxine deficiency has no observable effect on the conversion of hydroxyanthranilic acid to nicotinic acid, the action of this vitamin appears to be connected solely with the removal of the alanyl side chain at the kynurenine level. 

The activities of both kynurenine hydroxylase and kynureninase are only slightly higher than that of tryptophan dioxygenase under basal conditions, and increased tryptophan dioxygenase activity in response to glucocorticoid action is accompanied by increased accumulation and excretion of kynurenine, hydroxykynurenine and their transamination products, kynurenic and xanthurenic acids. Impairment of the activity of either enzyme may impair the onward metabolism of kynurenine and so reduce the accumulation of aminocarboxymuconic semialdehyde, and hence the synthesis of NAD. 

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). 

Kynurenine, which is formed from the formyl derivative by the action of formamidase, may be metabolized to a quinoline derivative, kynurenic acid. Alanine may be removed from kynurenine by kynureninase to form anthranilic acid. 

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