Biosynthesis anthranilic acid

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... 

Anthranilic acid (Figure 6.106) is a key intermediate in the biosynthesis of L-tryptophan (see page 126) and so contributes to the elaboration... 

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... 

The Rutaceae oxazoles are evidently derived from /V-nicotinoyl-p-(p-hydroxy)-phenylethylamide (51), with the exception of balsoxin (25) and texamine (26) in which the nicotinoyl moiety is replaced by benzoyl. The condensation of these tyramine and nicotinic acid residues does not represent any major departure from the standard routes of alkaloid biosynthesis in the Rutaceae, for it has long been recognized that the alkaloids of this family are all derived from either phenylalanine (52), tyrosine, (53), or anthranilic acid (54) (22), the latter being the acknowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a convergence of the two predominant modes of alkaloid biosynthesis in the family. 

Anthramycin is a benzodiazepine alkaloid with potent antitumor and antibiotic activity produced by the thermophilic actinomycete Streptomyces refuineus sbsp. thermotolerans. Using a genome-scanning approach, the biosynthesis was found to involve condensation of 4 methyl-3-hydroxy anthranilic acid 136 and a... 

Anthocyanins, biosynthesis of, 268 Anthranilic acid, 264, 266 conversion to tryptophan, 259, 265 formation of, 263... 

Fig. 12. Metabolic pathways leading to the biosynthesis of phenylalanine, anthranilic acid, and cyclopenin in Penicillium cyclopium (67). Symbols in parenthesis indicate observed feedback inhibition (-) or activation (-I-) of enzyme activities by L-amino acids. Number in circles (pkat/cm of mycelial area) represent either in vitro activities of the enzymes indicated or the rate of alkaloid formation in vivo. All data were measured after 7 days of growth in surface cultures. E 4-P, Erythrose 4-phosphate PEP, phosphoenolpyruvate DAHP, 3-deoxo-D-arabiuoheptuIosonic acid-7-phosphate InGP, inositol glycerophosphate SAM, 5-adeno ylmethionine.

Simulation of biosynthesis of phenazine pigments through the dimerization of substituted anilines by symmetrical carbon carbon pairing leads to substituted phenazines. Thus, oxidation of anthranilic acid with manganese(IV) oxide or lead(IV) oxide affords phenazine-l,6-di-carboxylic acid in 16% yield. ... 

Highly significant results have been obtained by Monkovic and Spenser 160) from a study of the biosynthesis of dictamnine using tracer methods. Mature plants of Dictamnus albus incorporate carboxyl- C-labeled anthranilic acid to give radioactive dictamnine, specifically labeled at C-4, strongly supporting the derivation of the alkaloid directly from anthranilic acid failure to incorporate radioactivity from tryptophan-jS- C shows that the 4-hydroxyquinoline unit is not derived... 

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). 

Phenylalanine and tyrosine acts as precursor for opium alkaloid biosynthesis. Tryptophan is a significant source of Vinca alkaloids. Alkaloids are derived from anthranilic acid, which is an intermediate in biosynthesis of tryptophan. Some alkaloids are derived from acetate, terpene or shikimic acid. Shikimic acid is a significant metabolite as most of the aromatic constituents are derived from shikimic acid pathway. 

Attention is drawn to reviews which include or are concerned wholly with biosynthesis Menispermaceae alkaloids, morphine alkaloids, and one which surveys the role of anthranilic acid in the biosynthesis of many alkaloid types. An excellent book on alkaloid biosynthesis edited by Mothes and Schiitte has appeared during 1969. ... 

C]Tryptophan gave inactive alkaloids but tritiated 2,4-dihydroxy-quinoline (34) and its N-methyl derivative were incorporated into (47) (0.009 % and 0.020% respectively) an early route had suggested the derivation of what was essentially (34) from tryptophan. Radioisotope dilution showed the presence of both these quinoline precursors together with iV-acetyl- and N-methyl-anthranilic acid in A. baueri. A satisfactory incorporation of N-methylanthranilic acid into (47) was found in Evodia xanthoxyloides, and this, together with its natural occurrence, indicates that early methylation may be important in the biosynthesis of acridone alkaloids. 

Benzodiazepine Alkaloids.—Cyclopenin (49) and cyclopenol (50) are isolated from Penicillium cyclopium. Their biosynthesis would appear to involve one molecule of phenylalanine and one of anthranilic acid and indeed the biosynthetic pathway to viridicatin and viridicatinol in Penicillium viridicatum from these two amino-acids has (49) and (50) as intermediates. ... 

The isolation of alkaloids bearing the 8-hydroxyquinoline moiety prompted postulation (17) of a biosynthetic pathway to 1 from the amino acid tryptophan, for which chemical analogies are known (22) (Scheme 2). It should be noted, however, that, in general, quinolines are biosynthesized from anthranilic acid (14). Biosynthesis of broussonetine (4) would involve condensation of two molecules of 1 with a molecule of acetyl-CoA followed by cyclization, as depicted in Scheme 3. 

Earlier theories of the biosynthesis of quinoline alkaloids found in the Rutaceae have been discussed in Volume IX of this treatise, and the first experimental results using radioactive tracers were also reviewed. Spenser and his collaborators showed that anthranilic acid is incorporated intact into dictamnine in Dictamnus albus and that C-10 and C-ll (cf. 328) are derived from C-l and C-2 of acetate, respectively (220). Matsuo et al. (221) demonstrated almost simultaneously that the quinoline ring of skimmianine in Skimmia japonica was formed similarly. Since then, the biosynthesis of furo- and isopropyldihydrofuroquinoline alkaloids has been studied intensively, with particular interest in the origin of the C2 and C5 side chains present at the 3-position of the quinoline ring of these alkaloids. 

The biosynthesis of 2-alkyl- and 2-arylquinoline alkaloids was investigated by Luckner and co-workers. For example, anthranilic acid was incorporated intact into 2-heptyl-4-hydroxyquinoline 339 in the microorganism Pseudomonas aeruginosa. Acetate and malonate are also precursors, and degradation experiments showed that the side chain was... 

Quinazoline Alkaloids.— The biosynthesis of vasicine (=peganine) (163) has been investigated in Adhatoda vasica (Acanthaceae) and Peganum harmala (Zygo-phyllaceae). In both plants the anthranoyl portion is known to derive from anthranilic acid [the reported incorporation of tryptophan (0.017 %) suggested as via anthranilic acid seems of questionable significance]. The remaining atoms of vasicine, however, appear to arise by different pathways in the two plants. 

Nitrogen metabolism plays a critical role in the biosynthesis of the streptothricin-type antibiotic nourseothricin in Streptomyces noursei [102]. Glutamine synthetase is repressed in this organism by a high concentration of ammonium ions. After the ammonium ion is depleted from the medium, derepression of the enzyme occurs. O-aminobenzoic (anthranilic) acid stimulates nourseothricin production and has a marked effect on regulation of enzymes responsible for nitrogen metabolism [102]. 

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