Derived from Tryptophan and Anthranilic Acid

Metabolites Derived from Tryptophan and Anthranilic Acid 

Tryptoquivaline (FTC, 74), C29H30N4O7, mp 155-157°C, [ot] +130°, exhibits absorption maxima at 228, 275, 305, and 317 nm in the UV spectrum. From the IR spectrum the presence of hydroxy, 7-lactone, ester, and amide groups in the molecule is expected. The NMR spectrum indicates the presence of one each of 

FTC tests positive with triphenyltetrazonium chloride (TTC), suggesting the presence of a hydroxylamine group. Methanolysis (0.5% HCl) gives a deacetyl derivative (75), mp 252-253°C, for which the TTC test is still positive and the UV spectrum is unchanged. On the other hand, a carboxyl band of the lactone is shifted from 1790 to 1765 cm , which suggests tryptoquivaline is not the simple acetate of 75. 

The intermediate hydroxy-y-lactone probably has undergone acyl transfer to the more stable trans disubstituted hydroxy-8-lactone. The p-bromophenyl-urethane derivative of 75, mp 196-198°C, (TTC negative) was utilized in determination of the structure and of the relative configuration by X-ray analysis (153). 

Hydrolysis of tryptoquivaline in methanolic alkali (0.1% KOH) produces an uncharacterized carboxylate which on acidification is transformed to the hy-droxy-y-lactone (CO, 1800 cm ). nip 175-176°C, [a] -142°. The new 7-lactone appears to be C-12-epitryptoquivaline (76) and shows that epimerization occurs prior lactone ring opening. 

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VII. Metabolites Derived from Tryptophan and Anthranilic Acid... 

Groger, D. Alkaloids Derived from Tryptophan and Anthranilic Acid. In Encyclopedia of Plant Physiology, New Series, Vol. 8 (Bell, E. A., B. V. Charlwood, eds.), p. 128. Berlin-Heidelberg Springer-Verlag. 1980. 

Grocer, D., Alkaloids derived from tryptophan and anthranilic acid, in Secondary Plant Products (E. A. Bell and B. V. Chari-wood, eds.). Encyclopedia of Plant Physiology, N. S., Vol. 8, 128-159, Springer-Verlag, Berlin, 1980. 

Groger, D. Alkaloids derived from tryptophan and anthranilic acid. In Encyclopedia of Plant Physiology, New Series, Vol. 8, Secondary Plant Products (E. A. Bell, B. V. Charlwood, eds.), pp. 128-159. Springer, Berlin-Heidelberg-New York 1980 Johne, S., Groger, D. Natiirlich vorkommende Chinazolin-Derivate. Pharmazie 25, 22-44 (1970) Luckner, M., Johne, S. Alkaloids derived from anthranilic acid. In Biochemistry of Alkaloids (K. Mothes, H. R. Schiitte, M. Luckner, eds.), Deutscher Verlag der Wissenschaften, Berlin 1985... 

The antibiotic tryptanthrin (53) has been biosynthesized from 1 mol of tryptophan and 1 mol of anthranilic acid. Upon feeding tryptophan and substituted anthranilic acids, or substituted tryptophans and anthranilic acid, the expected derivatives of 53 were isolated. The enzymes involved in the biosynthesis of 53 had no specificity for these substrates, with the exception of bromotryptophan. The anthranilic acid moiety used during biosynthesis results from tryptophan degradation 131,172). 

Evodiamine (67) and rutaecarpine (63) are derived, in Evodia rutae-carpa, from tryptophan (122), anthranilic acid (117) and formic acid 224) (see Scheme 10). After administration of [ " CH3]-methionine, 99% of the label was found at C-13b of rutaecarpine, while in evodiamine, the label is distributed between C-13b and the N-methyl group. Surprisingly, the level of specific incorporation of label in (67) is lower than that in (63) therefore. 

Streptonigrin.—Details of a study of the biosynthesis of streptonigrin (139) that had earlier been published in preliminary form (cf. Vol. 9, p. 24 Vol. 10, p. 23) are now available in full papers.51 52 In essence, the new results are that labelled anthranilic acid was not incorporated into streptonigrin (139),51 that l-rather than D-tryptophan was a precursor, and that label from C-7a in tryptophan (94) appeared, it was deduced, at C-8 in (139).52 The exclusive labelling of C-8 by tryptophan indicates that rings A and B do not derive from this amino-acid. These rings do not derive from phenylalanine and tyrosine, and negative results have been obtained with shikimic acid due, at the least, to poor cellular uptake.51... 

Preliminary results99 indicated that 11-demethyltomaymycin (118) had a similar genesis to anthramycin (116) from tryptophan and tyrosine, and these results have now been published in full.100 Tryptophan has been shown to provide ring A, presumably by catabolism through anthranilic acid. The results99,100 are summarized in Scheme 12. It is to be noted that methionine provides only the aromatic O-methyl group [in anthramycin there is an extra carbon present in the unit related to (119) which derives from methionine see above]. Further evidence from incorporation of labelled tyrosine indicates that the C7 unit (119) derives from seven tyrosine carbon atoms. The incorporation of L-[l-14C,2,3-3H2]tyrosine (tritium distribution H-2, 50% H-3-pro-S, 41.5% H-3-pro-R, 8.5%) with loss of half the tritium label was interpreted reasonably as involving loss only of the C-2... 

The indole moiety of the terpenoid indole alkaloids originates from tryptophan, an aromatic amino acid, which is derived from chorismate via anthranilate. Chorismate is a major branching point in plant primary and secondary metabolism. Here the shikimate pathway (Fig. 6) branches into different pathways (Fig. 7), among others leading to the aromatic amino acids tyrosine, phenylalanine, and tryptophan. 

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). 

This approach though also has some complications, particularly when the alkaloid has more than one nitrogen and more than one biosynthetic amino acid precursor unit. For example, evodiamine and rutaecarpine, from the fruits of Euodia mtaecarpa (Rutaceae), can be classified as alkaloids derived from tryptophan. In addition, one of the nitrogen atoms of each alkaloid is derived from an anthranihc acid unit. Therefore, these alkaloids can be classified as alkaloids derived fiom tryptophan and as alkaloids derived from anthranilic acid. In this volume, these alkaloids are discussed in Chapter 2.19 as alkaloids derived from tryptophan. 

It is interesting that harmine, which is derived from tryptophan (Section 2.6), coexists with vasicine (peganine), which is derived from an anthranilic acid precursor in P. harmala.Th.uSy tryptophan in which the benzene moiety was labeled with was fed in the same way as described above to P. har-mala, and it was found that the was incorporated into vasicine (peganine), although the incorporation rate was low (0.071%). Thus, it was estimated that this plant also possesses the biosynthetic pathway to convert tryptophan into anthranilic acid. 

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. 

Presently, alkaloids are classified into three main categories as shown in Fig. 8.2 [6]. This chemical classification of alkaloids is universally adapted and mainly depends on the type of heterocyclic ring structure present (Fig. 8.3). Alkaloids are further classified according to the amino acids (or their derivatives) from which they originate (Fig. 8.4) [6]. The most important classes are derived from the amino acids, ornithine and lysine, or from the aromatic amino acids, phenylalanine and tyrosine, or from tryptophan and a moiety of mavelonoid origin. A number of alkaloid-based compounds are also derived from anthranilic acid or from nicotinic acid. 

Kynurenine Metaholism. Kynurenine may be metabolized in five ways acetylation to iV -acetylkynurenine,i decarboxylation to kynuramine, oxidation to 3-hydroxykynurenine, cyclization to a quinoline derivative, and cleavage to yield anthranilic acid." The oxidation, cyclization, and cleavage reactions are components of major pathways of tryptophan metabolism. Ommochrome is composed of a series of heterocyclic condensed ring systems that have been shown to be derived from tryptophan via kynurenine. The individual steps in the enzymatic formation of the pigments have not separated. ... 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

Alkaloids derived from L-tryptophan hold the indole nucleus in a ring system. The ring system originates in the shikimate secondary compounds building block and the anthranilic acid pathway. It is known that the shikimate block. 

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

Of all the alkaloid-producing families, one of the most prolific is the Rutaceae (Waterman, 1975). The alkaloids obtained included 1-benzyltetrahydroisoquinoline, simple tryptophan derivatives, imidazoles and, most commonly, quinoline alkaloids originating from anthranilic acid. The Rutaceae was the only family in which the direct use of anthranilic acid in alkaloid production occurs to any extent. 

All naturally occurring benzodiazepines are biosynthesized from anthranilic acid. The benzodiazepine moiety is formed by reacting this central precursor with derivatives of phenylalanine (cyclopenin group), tyrosine (tomaymycin-anthramycin group), glutamine (auranthine), or tryptophan plus another molecule of anthranilic acid (asperlicin). Intensive biosynthetic work has been published for the cyclopenin and tomaymycin-anthramycin groups only. 

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