Anthranilic acid, and tryptophan

Haskins and Mitchell (365) found that a Neurospora mutant blocked between anthranilic acid and tryptophan accumulated anthranilic acid when... 

Several individual groups of alkaloids incorporate terpenoid units. For example, acronycine (Section 9.3) and reserpine (Section 2.10) incorporate C5- or Cjo-based terpenoid units, respectively. However, the origin of the nitrogen of these alkaloids is amino acids (anthranilic acid and tryptophan, respectively), so these alkaloids are not included in this chapter. 

Most aromatic compounds in plants are derived from shikimic acid metabolism many of these substances are phenols. Compounds derived from this pathway are extensively modified and considered under other classes of plant secondary metabolites. Although many types of secondary compounds are produced from intermediates of the shikimic acid pathway (e.g., certain naphthoquinones and anthraquinones discussed in Chapter 6), most are derived from four aromatic amino acids phenylalanine, tyrosine, anthranilic acid, and tryptophan. Aromatic compounds that arise from the shikimic acid pathway usually can be distinguished from those of other origins by their substitution patterns and by a knowledge of the compounds with which they co-occur. 

Fig. 31.1. Biosynthesis of anthranilic acid and tryptophan (Atta-ur-Rahman and Basha, 1983 used with permission of the copyright owner, Oxford University Press, Oxford).

The biosynthesis and metabolism of nicotinic acid in disease has received little attention metabolic studies deal mainly with normal animals and man (01, R5). After a tryptophan load dose, the main catabolites in the urine are nicotinuric acid, N1-methylnicotinamide, nicotinamide, quinolinic acid, kynurenine, 6-pyridone, anthranilic acid, and 3-hydroxyanthranilic acid. These excretory products were estimated... 

The next stage in the formation of the aromatic amino acids involves the conversion of shikimic acid to prephenic acid (XV) and anthranilic acid (XVI). The conversion of prephenic acid to phenylalanine and t3Tosine, and that of anthranilic acid to tryptophan are fairly well understood and... 

Boyland and Williams (B18) loaded 10 normal controls with 10 g DL-tryptophan. In spite of the fact that it is essential to use L-tryptophan in studies of this type and although data on excretion of kynurenic and xanthurenic acids are lacking, at least 5% was recovered as increased kynurenine, 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyan-thranilic acid, free and conjugated. It should be pointed out that in these studies only a low percentage of the ingested dose of tryptophan was found in the form of urinary metabolites. The remainder, approximately 93-94%, of the load could not be recovered. 

Anthranilic acid and indole are precursors of tryptophan in numerous microorganisms and fungi (e.g., 5, 263, 264, 602, 741, 783, 785, 816, 854, 855, 876), and it is probable that anthranilic acid is derived, with intermediate steps, from the common precursor, CP of diagram 1. The conversion of anthranilic acid to indole and tryptophan has been shown unambiguously in Neurospora with the use of isotopic techniques (93, 663). There may, however, be other pathways for tryptophan biosynthesis (45, 702). Tryptophan can, for example, be formed by transamination of indolepyruvic acid (e.g., 470, 912), which might be formed other than via anthranilic acid. Thus aromatic-requiring mutants have been found which accumulate unidentified indole compounds (307). 

Both anthranilic acid and hydroxyanthranilic acid can be formed from tryptophan in insect mutants, and both are conjugated with glycine to give substituted hippuric acids (796), whereas in plants or bacteria anthranilic acid tends to be conjugated as the /3-glucoside (848). 

Fujigaki, S., Saito, K., Takemura, M., Fujii, H., Wada, H., Noma, A., and Seish-ima, M., Species differences in L-tryptophan-kynurenine pathway metabolism Quantification of anthranilic acid and its related enzymes, Arch. Biochem. Biophys., 358, 329, 1998. 

Because shikimic acid does not enter into mammalian metabolism, its synthesis and use are clear targets at which to aim selective toxicity. In bacteria, shikimic acid arises by cyclization of the carbohydrate 3-deoxy-2-oxo-D- mAzVzoheptulosonic acid 7-phosphate, which is formed by the condensation of erythrose 4-phosphate and phosphoenolpyruvic acid. Shikimic acid undergoes biosynthesis to chorismic acid (4.55) which is the enolpyruvic ether of raw5-3,4-dihydroxy cyclohexa-1,5-diene-1-carboxylic acid. As its name indicates, this acid sits at a metabolic fork, the branches of which lead to prephenic acid, to phenylalanine (and hence to tyrosine), to anthranilic acid (and hence tryptophan), to ubiquinone, vitamin K, and/ -aminobenzoic acid (and hence folic acid). 

The antibiotic tryptanthrin (103) has been biosynthetically prepared from one mole of tryptophan and one mole of anthranilic acid. Feeding tryptophan plus substituted anthranilic acids, or substituted tryptophans plus anthranilic acid has resulted in the generation of the expected tryptanthrin derivatives. No substrate specificity (except for bromotryp-tophan) was observed in the enzymes involved in tryptanthrin biosynthesis. The anthranilic acid moiety of these compounds is the result of tryptophan degradation (65, 183). 

For further investigation of L-tryptophan biosynthesis, labelled antbranilate waus used. C-labelled anthranilic acid is converted uniformly to L-tryptophan in plant tissues. Furthermore, labelled lAA was formed from 3- 0-L-tryptophan. Both metabolic sequences are subject to interference by indole metabolites (intermediates of lAA biosynthesis) and by phenols. p-Coumario acid - one of the phenolic substances that inhibit cell elongation - depresses the formation of tryptophan from C-anthra-nilic acid, whereas caffeic acid, which enhances cell elongation, stimulates the incorporation of anthranilic acid into tryptophan (Table 2). Thus, one control effect in the action of phenols on plant growth may be influence on L-tryptophan biosynthesis. 

In the aromatic amino acid biosynthesis, chorismic acid (51) is converted into anthranilic acid, which would be a potential precursor providing both nitrogens for the ring as well as the aromatic system of phenazines. However, anthranilic acid and other proposed intermediates like quinic acid, tryptophan, tyrosine, and phenylalanine have been questioned on the basis of studies of mutants of phenazine producing organisms with blocked catabolism of these various possible intermediates. 

Tryptophan Biosynthesis. Tryptophan is another of the amino acids required by animals but synthesized only by plants and microorganisms. The synthesis of tryptophan in microorganisms has been outlined in recent years, but some of the reactions are still quite obscure. The known intermediates include shikimic acid, anthranilic acid, and indole. The mechanism of the conversion of shikimic acid to anthranilic acid has not been elucidated. 

Stanier and Hayaishi suggest that there are two general pathways for the oxidative catabolism of tryptophan, one through anthranilic acid and catechol, referred to as the aromatic pathway and the other through kynurenic acid, termed the quinoline pathway. These pathways have been established to a reasonable degree of certainty in bacterial enzyme systems, but are not so clearly evidenced in the vertebrate organism. 

When we come to tryptophan, which lies after shikimic acid, anthranilic acid and indole are found to be intermediates in the synthesis. The condensation of indole with serine to give tryptophan is brought about by the action of a specific enzyme, indole-ligase or tiyptophan desmolase, whose coenzyme is pytidoxal phosphate (this enzyme is not to be confused with tryptophanase which splits tryptophan into indole and pyrwoic acid). 

Figure 1.6a. Structures of some Rutaceae alkaloids. This order is recognized for accumulating alkaloids derived from different biosynthetic pathways, e.g., from anthranilic acid, tyrosine, tryptophan, and histidine.

Early studies of the biosynthesis of L-tryptophan (3) established that both anthranilic acid and indole were able to replace L-tryptophan as a growth factor for some bacteria. The suggestion that these compounds were normal precursors of the aromatic amino acid was confirmed by Tatum, Bonner and Beadle " who showed that some L-tryptophan requiring mutants of Neurospora sp. responded to anthranilic acid or indole whilst others responded only to indole and accumulated anthranilic acid. Somewhat later other mutants were found which were blocked between indole and L-tryptophan and accumulated indole in the culture medium. 

Role of Riboflavin. Riboflavin deficiency has been found to produce abnormaUties in the metabolism of tryptophan (307-311). The deficiency leads to an increased excretion in the urine of kynurenine, anthranilic acid, and kynurenic acid and its conjugates (308, 309). In liver and kidney slices riboflavin deficiency leads to a decrease in indolepyruvic acid accumulation and an increase in the production of kynurenic acid and anthranilic acid from L-kynurenine (310, 311). The deficiency was also found to... 

With chorismic acid an important junction in the shikimic acid pathway has been reached. For as the Greek name implies (chorizo = split), the synthetic route divides into two branches after this substance. One branch leads via anthranilic acid to tryptophan, and from it to the... 

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