Tryptophan degradative pathway

It was discovered in 1998 that expression of IDO activity in the mouse fetus represses the maternal T-cell activity and hence protects the fetus from the maternal immune system. Pregnant mice treated with the IDO inhibitor 1-methyltryptophan rejected the embryos via their immune system, thus either IDO itself or a product of tryptophan catabolism is able to suppress the maternal T-cell activity. IDO is also expressed in response to interferon 7 from activating T-cells, inhibiting T-cell proliferation and contributing toward the antiviral activity of interferon 7. The end product of the L-tryptophan degradation pathway, quinolinic acid, has neurological effects, hence the IDO pathway is implicated in several mammalian regulatory pathways. 

Of the parasitic diseases the most devastating one is malaria with a worldwide death toll of more than a million people. It is transmitted by the mosquito. To combat this, the life cycle and metabolism of the parasite Plasmodium falciparum is affected through a reduction in the synthesis of xanthurenic acid (92). Xanthurenic acid, required for gametogenesis and fertility of the parasite, is synthesized in the tryptophan degradation pathway through the PLP-dependent enzyme kynurenine aminotransferase. Hence, this enzyme is a target for the development of antimalarial drugs. 

Colabroy KL, TP Begley (2005) Tryptophan catabolism identification and characterization of a new degradative pathway. J Bacteriol 187 7866-7869. 

The degradative pathways of two of these seven amino acids deserve special mention. Tryptophan breakdown is the most complex of all the pathways of amino... 

Figure 23.30. Tryptophan Degradation. The pathway for the conversion of tryptophan into alanine and acetoacetate. 

It was only many years after the discovery of tryptophan that a plausible degradative pathway could first be outlined, but during this early period a few tryptophan metabolites were identified. The long-known (559) kynurenic acid (structure, diagram 20 cf. 408) was shown in 1904 to be derived from tryptophan (220), but the considerable amount of work on kynurenic acid formation (reviewed by Neubauer, 637) gave few useful results. Neubauer (637), however, made the plausible (and correct) suggestion that it was derived from o-aminobenzoylpyruvic acid (structure, diagram 20). 

VIII. Tryptophan Degradation by the Enter.a.mine-Serotonin Pathway ... 

Thomas and Stocker118 recently reported on studies supporting the proposal that induction of tryptophan degradation along the kynurenine pathway in human monocytes and macrophages by interferon-y represents a novel extracellular antioxidant defense that acts to prevent inadvertent oxidative damage to host tissue during inflammation. 

The presence of another contaminant peak in L-tryptophan implicated in EMS was detected upon HPLC with both UV and FL analyses by Toyo oka et al.9 and was characterized as PAA by Goda et al.7 Adachi et al.15 studied the metabolism of PAA in rats and described four metabolites of PAA in the urine (N-(hydroxyphenyl)glycine, N-phenylglycine, 3-(phenylamino)lactic acid, and 3-(hydroxy-phenylamino)-lactic acid). The results suggested that the degradation pathway of PAA was similar to that of phenylalanine. Other studies with PAA are described in Section 11.10. 

The hydroxylation pathway of tryptophan. The pathway of tryptophan hydroxylation in the 5 position and its products are shown above. These include the formation of serotonin and its degradation product, 5-hydroxyindole acetate, as well as melatonin formation. (See text for more detail.)... 

Viani and Horman (1976) found indole on roasting serotonin (hydroxytryptamine, 2-aminoethyI-I//-indol-5-ol), present as an amide in the waxes surrounding the coffee bean and which behaves like the related tryptophan. A pathway showing its formation in the thermal degradation of phenylalanine at 300 °C has been published by Kato et al. (1971). 

Two reports raise concern over the authenticity of the identification of 5-HT in some nematodes. Willett (163) summarized a series of experiments on Panagrellus redivivus, showing that 5-HT itself could not be detected in this nematode instead there is a compound resembling 5-HT, but heavier by 58 mass units. In A. galli, 5-HTP, 5-HIAA and 5-HT were identified chromatographically in extracts of whole worms, but attempts to produce 5-HT from radiolabeled tryptophan resulted in a compound clearly distinct from 5-HT (172). Complete chemical characterization will reveal whether these compounds are important signaling molecules or are intermediates of the degradative pathways. 

Among the existing degradative pathways for tryptophan, one is known as the kynurenine route, Fig. (1). The word kynurenines is used to define the intermediates of this route which account for more than 90% of the whole tryptophan metabolism in man [4], and for 95% of dietary tryptophan [5], So, the intermediates of the kynurenine pathway are quite important quantitatively. Among these, kynurenic and quinolinic acids have been extensively studied as regards their neuroactivities [6-13]. 

If the dietary levels of niacin and tryptophan are insufficient, the condition known as pellagra results. The symptoms of pellagra are dermatitis, diarrhea, dementia, and, finally, death. In addition, abnormal metabolism of tryptophan occurs in a vitamin B6 deficiency. Kynurenine intermediates in tryptophan degradation cannot be cleaved because kynureninase requires PLP derived from vitamin B6. Consequently, these intermediates enter a minor pathway for tryptophan metabolism that produces xanthurenic acid, which is excreted in the urine. 

The simple quinazoline derivatives produced by Pseudomonas are formed in the course of tryptophan degradation ( quinazoline pathway ). Tryptophan is first converted to formylkynurenine and then to A-formylaminoacetophenone, which forms 4-methylquinazoline with ammonia or loses the formyl group to give 2-aminoacetophenone. After reacylation and cyclization with ammonia this latter product yields the other derivatives of 4-methylquinazoline (58,59). 

Tryptophan is an essential amino acid which is ingested by Americans in quantities that exceed the normal daily requirements for protein synthesis (Rl), and considerable amounts are converted to nonprotein substances such as nicotinic acid and serotonin (Fig. 1). The tryptophan-niacin pathway, which is also known as the kynurenine pathway (Fig. 1), is important for production of the vitamin, nicotinic acid, and provides also a means for degrading tryptophan to acetoacetyl-CoA, carbon dioxide, and ammonia (P7). The amount of tryptophan metabolized by the various pathways available depends greatly on the amount of... 

There are no reports of the occurrence in higher plants of the enzymes or intermediates of the kynurenine degradative pathway. Wiltshire (1953) did report that pea seedling slices metabolized tryptophan and produced a product which he suggested might be 3-hydroxykynurenine. 

A small number of simple substituted quinazolines can be formed in the course of tryptophan degradation by microorganisms (131, 132). In Pseudomonas species, three pathways of tryptophan degradation are known the aromatic pathway in Ps. fluorescens, the quinoline pathway in Ps. acidovorans, and the quinazoline pathway in Ps. aeruginosa. Investigations with [P- C]-tryptophan have provided evidence for a new pathway from tryptophan through the intermediates, formylkynurenine and N-formylaminoacetophenone, forming 4-methylquinazoline with ammonia and free 2-aminoacetophenone. Reacylation of the product and cyclization with ammonia produces other derivatives of 4-methyl-quinazoline. 

In a group of bacteria tryptophan degradation follows another pathway and yields indole, pyruvic acid and ammonia (Fig. 245). 

Certain microorganisms degrade L-tryptophan (in some cases also D-trypto-phan) via kynurenic acid to compounds of primary metabolism (Fig. 265, quinolinic pathway of tryptophan degradation, in contrast to the aromatic pathway via 3-hydroxyanthranilic acid shown in Fig. 244). 

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