Tryptophan-derived Metabolites

The amino acid tryptophan provides the building block for some important 

Tryptophan and its relative indolylpyruvic acid (3.42) have been shown to precursors of hinnuliquinone (3.41), which is a pigment of Nodulisporium hin-nuleum. Typical of many fungal indoles in which alkylation by a dimethylallyl or isopentenyl group has occurred, mevalonate was also a precursor. However, the stage at which prenylation of a monomer or a dimer took place was unclear. Asterriquinone (3.43) from Aspergillus terreus and cochliodinol (3.44) from Chaetomium cochliodes are similar metabolites. Fission of the hydroxyquinone in the latter followed by lactonization leads to cochliodinone (3.45) in a sequence that is similar to that which inter-relates the terphenyls and pulvinic acids described in Chapter 7. 

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Behavioral disorders such as anorexia, sleep disturbances, and pain insensitivity associated with hyperammonemia have been attributed to increased tryptophan transport across the blood-brain barrier and the accumulation of its metabolites. Two of the tryptophan-derived metabolites are serotonin and quinolinic acid (discussed later). The latter is an excitotoxin at the N-methyl-D-aspartate (NMDA) glutamate receptors. Thus, the mechanism of the ammonium-induced neurological abnormalities is multifactorial. Normally only small amounts of NH3 (i.e., NH4 ) are present in plasma, since NH3 is rapidly removed by reactions in tissues of glutamate dehydrogenase, glutamine synthase, and urea formation. 

Dendrodoine (109) [80,81], the related aminoimidazole (110) analogue [82] and the recently reported oxadiazinone, alboinon (111) [83] were reported from Dendrodoa grossularia. There are structural similarities between these tryptophane-derived metabolites, the phenylalanine-derived metabolites (5), (6) and (7), and the tyrosine-derived metabolite... 

But it can be assumed that kororamide A is derived from the combinations of brominated tryptophan derived metabolite and proline derivative. Synthesis of kororamide A (141) is not reported in literature. 

When plants undergo various stresses, certain secondary metabolites, including defense compounds, accumulate. Several secondary metabolites such as terpenoid indole alkaloids, indole glucosinolate, nicotine alkaloids, and polyamines are known to accumulate through the induction of biosynthetic genes by jasmonates.898-900 MeJA also induces genes involved in the formation of tryptophan derivatives, terpenoid indole alkaloids.901 These compounds are known to be involved in defense response to pathogen attack as phytoalexins. 

From our investigation it is evident that abnormal excretion of tryptophan metabolites is not a typical feature of bladder tumor subjects, since human beings with neoplastic and nonneoplastic extrabladder urinary diseases have also been found to excrete spontaneously elevated amounts of tryptophan derivatives. It seems that the metabolic abnormality is not restricted to bladder tumors, but is rather more specific for patients with tumors of the upper urinary tracts and of the renal parenchyma. Actually 59% of these patients (Fig. 4) excreted abnormal amounts of kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. 

Seven of the 8 twins showed, after loading, an abnormal excretion of tryptophan derivatives, higher than that observed in the schizophrenic patients mentioned above. The excretory pattern of all tryptophan metabolites, independent of the monozygous or dizygous character, appears to be unusually elevated, indicating a biochemical lesion in both members of each pair of twins. 

These patients appear to excrete a slightly higher amount (8.9-12.3%) of tryptophan derivatives than normals (average 6.7%), The excretion ratios are different for each metabolite the highest ratio is found for 3-hydroxykynurenine and the lowest for 3-hydroxyanthranilic acid. 

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]. 

In this chapter we consider some important fungal metabolites that are biosynthesized by fungi such as Penicillium and Aspergillus species. These include the penicillin and cephalosporin p-lactam antibiotics. Some fungal metabolites derived from amino acids that have achieved notoriety because of their toxicity are described in Chapter 9 on mycotoxins. These include several tryptophan derivatives. Other compounds also derived from amino acids are to be found amongst the fungal pigments described in Chapter 7. 

Higher-Order Derivative Spectrophotometry of Tryptophan and Metabolites , in Progress in TTyptophan and Serotonin Research, edited by H. G. Schlossberger, W. Kochen, B. Linzen, H. Steinhart, 140-142. Berlin, New York Walter de Gruyter u. Co., 1984. 

The inability of 3-HAA or 3-hydroxyk5murenine to depress tryptophan incorporation into actinomycin is puzzling since these compounds are known tr tophan metabolites which can readily be pictured as intermediates in the conversion of tryptophan to 4-MHAA. The dilution studies with 3-HAA and 3-hydroxykynurenine might indicate that these tryptophan derivatives are not free intermediates in the synthesis of actinomycin. 

Appleton, D.R., Babcock, R.C., and Copp, B.R. (2001) Novel tryptophane-derived dipeptides and bioactive metabolites from the sea hare Aplysia dactylomela. Tetrahedron, 57,10181-10189. 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

Important indole derivatives (see Scheme 2) include (i) indigo, a vat dye known and widely used since antiquity, and originally obtained from indican, a (3-glucoside of indoxyl which occurs in some plants. Indigo is now prepared synthetically. Tyrian purple, a natural dye used since classical times, is 6,6 -dibromoindigo (ii) the numerous indole alkaloids, with complex derivatives such as yohimbine and strychnine (iii) tryptophan, an essential amino acid found in most proteins. Its metabolites include skatole and tryptamine and (iv) 3-indoleacetic acid, which is important as a plant growth hormone. 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

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