Kynurenine-3-hydroxylase

The disturbance of tryptophan metabolism in riboflavin deficiency, caused by impairment of kynurenine hydroxylase, can also result in reduced synthesis of NAD from tryptophan. This may therefore be a factor in the etiology of pellagra (Section 8.3.3.1). 

Figure 8.4. Pathways of tryptophan metaholism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynureninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic acid 167.1. CoA, coenzyme A.

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). 

Kynurenine Hydroxylase Kynurenine hydroxylase is an FAD-dependent mixed-function oxidase of the outer mitochondrial membrane, which uses NADPH as the reductant. The activity of kynurenine hydroxylase in the liver of riboflavin-deficient rats is only 30% to 50% of that in control animals, and deficient rats excrete abnormally large amounts of kynurenic and anthranilic acids after the administration of a loading dose of tryptophan, and, correspondingly lower amounts of quinolinate and niacin metabolites. Riboflavin deficiency may thus be a contributory factor in the etiology of pellagra when intakes of tryptophan and niacin are marginal (Section 8.5.1). 

Studies with [ C] tryptophan in animals and isolated hepatocytes show that leucine does inhibit the synthesis of NAD from tryptophan, inhibiting metabolism at the level of kynurenine hydroxylase and kynureninase, causing the accumulation of intermediates. In isolated hepatocytes, the more... 

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. 

Bender DAand McCreanorGM (1985) Kynurenine hydroxylase a potential rate-limiting enzyme in tryptophan metabolism. Biochemical Society Transactions 13,441-3. 

The enzyme indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, kynurenine is then converted to quinolinic acid via the intermediate 3-HK by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are induced by the type-1 cytokine IFN-y. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation, the activation of the type-1 immune response and the regulation of the tryptophan metabolism (Mellor and Munn, 1999). It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan (Munn et al., 1999). In contrast to the type-1 cytokines, the type-2 cytokines IL-4 and IL-10 inhibit the IFN-y-induced IDO-mediated tryptophan cataboUsm (Weiss et al., 1999). IDO is located in several cell types including monocytes and microglial cells (Alberati et al., 1996). An IFN-y-induced, IDO-mediated decrease of CNS... 

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