Tryptophan metabolites, biologically active

The indole ring is incorporated into the structure of the amino acid tryptophan [6912-86-3] (6) and occurs in proteins and in a wide variety of plant and animal metabolites. Much of the interest in the chemistry of indole is the result of efforts to understand the biological activity of indole derivatives in order to develop pharmaceutical applications. 

The effect of proteins on pollutant toxicity includes both quantitative and qualitative aspects. Experiments show that animals fed proteins of low biological value exhibited a lowered microsomal oxidase activity when dietary proteins were supplemented with tryptophan, the enzyme activity was enhanced. Alteration of xenobiotic metabolism by protein deprivation may lead to enhanced or decreased toxicity, depending on whether metabolites are more or less toxic than the parent compound. For example, rats fed a protein-deficient diet show decreased metabolism but increased mortality with respect to pentobarbital, parathion, malathion, DDT, and toxaphene (Table 6.4). On the other hand, rats treated under the same conditions may show a decreased mortality with respect to heptachlor, CC14, and aflatoxin. It is known that, in the liver, heptachlor is metabolized to epoxide, which is more toxic than heptachlor itself, while CC14 is metabolized to CC13, a highly reactive free radical. As for aflatoxin, the decreased mortality is due to reduced binding of its metabolites to DNA. 

The synthesis of indoles on soHd supports has been driven by the wide range of indole derivatives that occur in Nature [142-144], and by the biological activity of many indole derivatives of both natural and synthetic origin [145]. The indole scaffold appears in the amino acid tryptophan, the metabolites of which are important in the biochemistry of both plants and animals. In addition, the indole ring appears in many compounds that have found use as drugs, e.g., indomethacin [146], sumatriptan [147], and pindolol [148]. Synthetic approaches towards indoles on solid phases have also been reviewed elsewhere [149]. 

For the biosynthesis of a secondary metabolite at least one enzyme is required, changing the primary metabolite into a (specific) secondary product. However, in most cases more enzymes are involved, e.g. the number of enzymes for the biosynthesis of vinblastine, starting from tryptophan and geranyl diphosphate is higher than 25. Plants are thus not only a rich source of complex, biological active, fine-chemicals, but are probably an even more rich source of biocatalysts. Its potential in bioconversions is recognized [2]. 

The simplest unsubstituted indole and its methyl derivative, scatol, were found in some Lepiota and Tricholoma species. The probable biogenetic precursor of all indole metabolites is the amino acid tryptophan, widely distributed in fungi, or its derivative tryptamine, found in some species of Coprinus, Inocybe, Panaeolus, Sacrodon, and Boletus (7). Investigation of a strong biological activity characteristic of an animal hormone function revealed the presence 5-hydroxytryptamine (serotonin), which was found in large amounts in some Panaeolus and Amanita species. 

Compounds related to tr5 tophan were studied for effects on pyrrolnitrin production. The following compounds appeared to lower the amount of antifungal agent produced tryptamine, indole-3-acetic acid, and indole. No effect on the level of biological activity was seen with D,L-serine or shikimic acid. N-chloroacetyl tr5q)tophan enhanced the quantity of metabolite produced, probably by hydrolysis to tryptophan. 

Csipo et al.34 have described decreased serum tryptophan and elevated neopterin levels in patients with systemic sclerosis. Signs of chronic activation of cell-mediated immunity in systemic sclerosis were demonstrated by elevated neopterin levels.35 Neopterin is a biologically stable metabolite that reflects the increased synthesis of interferon-y. Interferon-y induces a decrease in serum tryptophan levels via the induction of IDO, so that the detection of a decrease in serum tryptophan levels seems to serve as a tool for evaluating activation of cellular immunity.36 Of interest is that the serum interferon-y level itself was not increased in systemic sclerosis.3738... 

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