Indoleamine pathway

Figure 49.1 Metabolism of tryptophan by the kynurenine pathway to produce NAD and NADP, or by the indoleamine pathway to produce serotonin and melatonin.

Serotonin (5-hydroxytryptamine) is produced from tryptophan by the indoleamine pathway. Serotonin is important for a feeling of wellbeing, and a deficiency of brain serotonin is associated with depression. The selective serotonin reuptake inhibitors (SSRIs) are a successful class of antidepressive drugs that prolong the presence of serotonin in the synaptic cleft, thereby stimulating synaptic transmission in neurones that produce a sense of euphoria. 

Tryptophan dioxygenase (Section 8.3.2) is only found in the liver other tissues have an indoleamine dioxygenase, with lower specificity, that catalyzes the same reaction. However, the pathway for onward metabolism of kynure-nine is found only in liver and mononuclear phagocytes, and induction of indoleamine dioxygenase by cytokines, such as interferon-y, leads to increased circulating concentrations and urinary excretion of kynurenine, with litde or... 

Indoleamine dioxygenase has been found in many tissues of mammals. It catalyzes the first and rate-limiting step in the main pathway of human tryptophan... 

Figure 28 The indoleamine 2,3 dioxygenase pathway of Trp metabolism. Molecular oxygen is incorporated into the pyrrole ring to yield M-formylkynurenine which is then degraded to kynurenine and formic acid...

A potential for endogenous excitotoxin produced in the CNS via tryptophan metabolism has been localised to microglia.97 Microglia contain indoleamine-2,3-dioxy-genase (the first enzyme in this pathway), which converts tryptophan to kynurenine, and which is induced in microglia and macrophages by IL-1 and infections.98 Inhibitors of quinolinic acid production such as 4-chloro-3-hydroxyanthranilate and ///-nitrobenzylalanine99 100 could probably be of therapeutic value. 

A. The patient, despite being put on a low-Phe diet, exhibits neurologic problems resulting from an inability to synthesize catecholamine and indoleamine neurotransmitters. This is caused by a deficiency in dihydropteridine reductase (DHPR). DHPR regenerates tetrahydro-biopterin (BH ), which is oxidized to dihydrobiopterin by phenylalanine hydroxylase, as well as tyrosine hydroxylase and tryptophan hydroxylase (tryptophan 5-monooxygenase). If phenylalanine hydroxylase were deficient, a diet low in Phe would alleviate the effects. Since the urinary biopterin concentration is elevated, a deficiency in GTP cyclohydrolase I is eliminated because that is an enzyme in the biosynthetic pathway of BH. Phe hydroxylase, Tyr hydroxylase, and Tip hydroxylase activities are low because of a lack of BH. ... 

From 1978 to 1985 renewed interest in tryptophan metabolism via the kynurenine-niacin pathway was generated by the findings of Hayaishi et al. and others of a second enzyme, namely, indoleamine-2,3-dioxygenase (IDO).2 3 This enzyme was found to be present in several nonhepatic tissues (lung, intestine, brain, and epididymis) and cells (blood monocytes, macrophages, and eosinophils). The enzyme normally has very low activity but is induced to very high activity by stimulation of immune systems with interferon-y1-8 or interleukin-2 (cytokines).9 Thus, inflammatory processes, infections, and immune stimulation that induce interferon-y could lead to... 

In many of the illnesses where serum tryptophan levels are diminished, it is evident that there is usually enhanced activity along the kynurenine pathway, often involving indoleamine-2,3-dioxygenase (IDO). This has a negative effect on the serotonin pathway. Indeed, many patients receiving interferon-y... 

Silver et al.58 have reported that during the active phase of EMS tryptophan metabolism via the kynurenine pathway was accentuated, probably secondary to induction of the enzyme indoleamine-2,3-dioxygenase. Indeed, patients with EMS generally have low plasma L-tryptophan and high plasma L-kynurenine and quinolinic acid levels. 

The first step of tryptophan catabolism is the oxidative cleavage of the indole ring of L-tryptophan, which is catalyzed by members of the family of pyrrole dioxygenases. A key member of this family, indoleamine-2,3-dioxygenase (IDO, see Fig. 1, EC 1.13.11.17), is expressed in all tissues except in the liver and produces the central metabolite kynurenine (KYN). Two different and competing branches of the pathway then further metabolize KYN the first pathway includes a family of enzymes called kynurenine aminotransferases (KATs), which produce kynurenic acid (KYNA) in a terminal branch. In a second arm, KMO (or kynurenine... 

Thomas, S.R., and Stocker, R., 1999. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Report. 4 199-220. 

Functional end products of the essential amino acid tryptophan arise mainly through two distinctive pathways. The major pathway is degradation of tryptophan by oxidation, which fuels the kynurenine pathway (See 02011). The second and quantitatively minor pathway is hydroxylation of tryptophan and its subsequent decarboxylation to the indoleamine 5-hydroxytryptamine (serotonin) and subsequently melatonin. The metabolites of the kynurenine pathway, indicated as kynurenines, include quinolic acid and kynurenic acid. Quinolinic acid is an agonist of the NMDA receptor (see also section on glutamic acid), while kynurenic acid is a nonselective NMDA-receptor antagonist with a high affinity for the glycine site of the NMDA receptor (see also section on... 

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