Enzyme 1- Tryptophan 2,3-dioxygenase

The heme enzyme, tryptophan dioxygenase, activates molecular oxygen to undergo the following reaction [Cragh (125), Yamamoto (215), Marks (128) ... 

Samples of (3R)- and (3S)-[3- Hi]tryptophans 331 have been converted to the corresponding kynurenines 336 using the enzymes tryptophan dioxygenase (EC 1.13.11.11) and formylkynurenine formamidase (EC 3.5.1.9). These have been used to investigate the fission of kynurenine 336 to anthranilic acid 300 and alanine 337 in H20 (337) (Scheme 85). Conversion of the alanine to acetate and assessment of sense of chirality indicated that... 

The activities of three enzymes, tryptophan dioxygenase, kynurenine hydroxylase and kynureninase, affect the rate of formation of aminocarboxymuconic semialdehyde, as may the rate of uptake of tryptophan into the liver. 

Examples include the liver enzymes, homogentisate dioxygenase (oxidase) and 3-hydroxyantliranilate dioxygenase (oxidase), that contain iron and L-trypto-phan dioxygenase (tryptophan pyrrolase) (Chapter 30), that utilizes heme. 

In animal studies, high levels of cortisol have been shown to induce (increase) the activity of the enzyme tryptophan 2,3-dioxygenase in the liver, thereby decreasing the bioavailability of tryptophan to the brain. It is interesting to note that low acute doses of a number of different antidepressants inhibit the activity of this enzyme and, as a result, increase brain tryptophan concentrations, thus stimulating 5-HT synthesis (Badawy and Evans, 1982). In this way a link between the two key monoamine neurotransmitters and the hormone may be seen namely, reduced brain NA activity leads to decreased inhibition of the HPA axis, while increased levels of cortisol reduce 5-HT activity in the brain. Activation of the HPA axis has also been shown to result in tissue atrophy, in particular of the limbic system s hippocampus, and a reduction in the levels of neurotrophic factors responsible for the maintenance and optimal function of brain neurons (Manji et al., 2001). In conclusion, manipulation of the HPA axis (Nemeroff, 2002) and stimulation of neurotrophic factor activity (Manji et al., 2001) might open up new avenues for the treatment of affective disorders. 

Miller, C. L., Llenos, I. C., Dulay, J. R. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 15 618-629, 2004. 

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. 

Cobaltn-Schiff base complexes, e.g. Co(salen),567 Co(acacen)568 and cobalt(II) porphyrins,569 e.g. Co(TPP), are effective catalysts for the selective oxygenation of 3-substituted indoles to keto amides (equation 249), a reaction which can be considered as a model for the heme-containing enzyme tryptophan-2,3-dioxygenase (equation 21).66 This reaction has been shown to proceed via a ternary complex, Co-02-indole, with probable structure (175), which is converted into indolenyl hydroperoxide (176). Decomposition of (176) to the keto amide (174) readily occurs in the presence of Co(TPP), presumably via formation of a dioxetane intermediate (177).569,56 Catalytic oxygenolysis of flavonols readily occurs in the presence of Co(salen) and involves a loss of one mole of CO (equation 251).570... 

Livers from mice were manually sectioned into 1 to 1.5 mm cubes. In contrast to liver homogenates or purified enzyme, liver slices did not require exogenous methemoglobin or ascorbic acid for activation of tryptophan dioxygenase. 

The first enzyme of the pathway, tryptophan dioxygenase (also known as tryptophan oxygenase or tryptophanpyrrolase), is rate-limiting under normal conditions. In isolated hepatocytes, the control coefficient for flux through the pathway of tryptophan dioxygenase is 0.75 and that for tryptophan uptake into the cells is 0.25 (Salter et al., 1986). 

Even without induction of tryptophan dioxygenase, impairment of the activity of either enzyme may impair the onward metabolism of kynurenine and thus reduce the accumulation of aminocarboxymuconic semialdehyde and synthesis of NAD. 

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. 

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. 

For many years tryptophan dioxygenase was considered a very important enzyme in the kynurenine-niaci n pathway. The induction of liver tryptophan dioxygenase by glucocorticoids and stabilization by elevated tryptophan levels were utilized in explaining elevated metabolite levels in a variety of conditions. This enzyme will be discussed in greater detail in another section. 

The more recent discovery that the enzyme indolamine dioxygenase (IDO) also is involved in the kynurenine-niacin pathway in nonhepatic tissues, such as lung, intestine, and epididymis, or in cells, such as monocytes, macrophages, and eosinophils, has been a major breakthrough. It has expanded the information about the utilization and involvement of tryptophan in cells considered to be active in immunologic reactivity and responses. 

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