6-Hydroxyanthranilic acid, from

M18. Musajo, L., Spada, A., and Coppini, D., Isolation of 3-hydroxyanthranilic acid from pathological human urine after administration of L-tiyptophan. J. Biol. Chem. 196, 185-188 (1952). 

Picolinic Carboxylase. An enzyme in liver decarboxylates the original carboxyl group of 3-hydroxyanthranilic acid from the oxidation product. The product of the decarboxylation is picolinic acid. Picolinic carboxylase has no known cofactors. The mechanism of its action is thought to involve a temporary loss of the double bond during decarboxylation. This permits rotation of the amino group into a position favoring condensation to form the pyridine ring (XII). 

Synthesis of 4-methyl-3-hydroxyanthranilic acid from tryptophan... 

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

Phenazines.—Results on the biosynthesis of microbial phenazines from shikimic acid (previously published in preliminary form cf. Vol. 5, p. 44 and Vol. 7, p. 27) are now available in full papers.53 Additional results are that 2,3-dihydro-3-hydroxyanthranilic acid (140) was not a precursor for iodinin (141), nor was... 

Figure 9-53 Determination of lymphocyte kynureninase activity levels using HPLC. Enzyme activity is measured by quantification of formation of the product, 3-hydroxyanthranilic acid (3-HA A). (A) 3-HA A standard (12.0 nmol/L). (fl), Lymphocyte homogenate blank. (C) Lymphocyte 3-HAA production after 5 min of incubation in presence of 3-hydroxy-kynurenine. Peaks 1,3-HAA unmarked peaks are unidentified components. (From Ubbink et al., 1991.)...

Animals and yeasts can synthesize nicotinamide from tryptophan via hydroxyanthranilic acid (52) and quinolinic acid (53, Fig. 6A) (31), but the biosynthetic capacity of humans is limited. On a diet that is low in tryptophan, the combined contributions of endogenous synthesis and nutritional supply of precursors, such as nicotinic acid, nicotinamide, and nicotinamide riboside, may be insufficient, which results in cutaneous manifestation of niacin deficiency under the clinical picture of pellagra. Exogenous supply of nicotinamide riboside was shown to promote NAD+-dependent Sir2-function and to extend life-span in yeast without calorie restriction (32). 

It was furthermore reported (K20) that nicotinic acid-deficient animals would grow only if given tryptophan, thus suggesting the conversion of tryptophan to nicotinic acid. Not only is tryptophan converted to nicotinic acid but also kynurenine and 3-hydroxyanthranilic acid. The peculiar degradation of the latter to pyridine derivatives gave rise to many interesting investigations. 3-Hydroxyanthranilic acid is derived from 3-hydroxykynurenine, another important tryptophan metabolite, the his-... 

The pieces of paper with 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid are each placed in an Erlenmeyer flask fitted with a ground-glass stopper and containing 3.8 ml distilled water. After 15-16 hours, 1 ml diazotized sulfanilic acid (0.5% in 2% hydrochloric acid mixed immediately before using with an equal volume of 0.5% solution of sodium nitrite in water) and 0.2 ml pyridine are added. The temperature must be held constant at 15° to obtain reproducible results. The color resulting from xanthurenic acid is read immediately at 510 mp, and of the other two derivatives after 60-80 minutes at 450 mp. 

A column of Amberlite IR-120, 0.9 X 28 cm, held constant at 37°C and formic acid-pyridine buffers are employed. With a buffer formic acid-pyridine 0.2 N, pH 2.50-2.60, kynurenic, xanthurenic, and o-amino-hippuric acids are eluted successively from the column. By increasing molarity and pH, respectively, to 0.3 N and 4.20 there emerge kynurenine, 3-hydroxyanthranilic acid, and 3-hydroxykynurenine, which are collected automatically in fractions of 2 ml. Figure 3 gives an example of chromatographic separation. 

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. 

Hydroxyanthranilic acid was shown to be present in the urine of patients suffering from the same disease (F3). 

Ogino and Ichihara (02) reported in 1957 the isolation in pure form of 5-hydroxyanthranilic acid and anthranilic acid from urine of patients with senile cataract. Bromine oxidation of 5-hydroxyanthranilic yielded quinoniminecarboxylic acid, which showed cataractogenic activity when injected in scorbutic guinea pigs. 

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). 

The results with Neurospora led Bonner and Yanofsky (94) to suggest that the conversion of hydroxyanthranilic acid to nicotinic acid went by way of Intermediates A and B of diagram 21. Quinolinic acid formation was thought to be a shunt or side reaction of intermediate A, slow conversion to nicotinic acid possibly providing an alternative pathway. A similar conclusion was drawn from experiments in the rat (971), and it is now generally agreed that the conversion of quinolinic acid to nicotinic acid is at best of the order of a side reaction (e.g., 685, 754, and in man, 397, 696). 

Isotopic experiments (763) with tryptophan labeled with N and deuterium in the indole ring have shown that quinolinic acid nitrogen is probably entirely derived from the indole nitrogen of tryptophan, and that scission of the benzene ring probably occurs between carbons 3 and 4. Presumably, therefore, the hydroxyanthranilic acid is converted to intermediate A without participation of a catechol-type intermediate, and it is possible that the phosphate-bond energy of hydroxyanthranilic acid phosphate (if this is in fact an intermediate) may contribute to the transformation. It is known... 

The relation of many of the simpler alkaloids to the aromatic amino acids is obvious. For example, germinating barley contains (241), besides tyrosine and tyramine, A -methyltyramine, JViV -dimethyltyramine (hordenine), and the trimethylammonium derivative (candicine). In this simple case the. AT-methylated derivatives are known to be derivable from isotopically labeled tyramine (538) and the methyl groups are known to arise from methionine by transmethylation (540, 586). Similarly AT-methyl derivatives of phenylethylamine, 3,4-dihydroxyphenylethylamine, and 3,4,5-trihy-droxyphenylethylamine are well known alkaloids (cf. review, 701). N-Methylated derivatives of tryptamine and hydroxytryptamine equally occur for example, eserine has an obvious relation to 5-hydroxy tryptamine. Methylated derivatives of metabolites of the aromatic amino acids also occur, for example, trigonelline (67), which is the betaine of nicotinic acid, and damascenine is probably similarly related to hydroxyanthranilic acid. 

Purification has been reported of phenoxazinone synthase, the enzyme which catalyses phenoxazinone formation from 4-methyl-3-hydroxyanthranilic acid (123) in the biosynthesis of actinomycin (124). Two forms of the enzyme, one of high and one of low molecular weight, were isolated. The relative amount of the... 

A stereoselective synthesis of tilivalline, a metabolite from klebsiella, has been achieved via intermediate 78 by coupling 3-hydroxyanthranilic acid (76) with pyrrolidine acetal (77).30... 

Fig. (4).The quinonoid compound, arising from 3-hydroxyanthranilic acid (auto)oxidation...

Fig. (7). The tricyclic lactone, arising from oxidative coupling between tyrosine and 3-hydroxyanthranilic acid...

Hydroxyanthranilic Acid. This was obtained from Hoffman-LaRoche (Basel) and used as purchased. 

The remaining atoms in anthramycin (166) can be identified with 4-methyl-3-hydroxyanthranilic acid (171), an intermediate in the biosynthesis of actinomycins from tryptophan.In accord, [7a- C]tryptophan was well incorporated into anthramycin. " ... 

BiosytMesis In animals tryptophan - kynutenine - 3-hydroxyanthranilic acid - quinolinic acid (pyri-dine-2,3-dicaiboxylic acid) - nicotinic acid - nicotinamide. In bacteria and higher plants from L- aspar-tic acid and a C3-unit, probably D-glyceraldehyde 3-phosphate. Also by cleavage of NAD. 

Both tryptophan and tyrosine fiamished melanin. Similar results were also obtained by Allegri et al. (3), who studied melanin synthesis from tryptophan and tyrosine spectrophotometrically. From tyrosine, p-hydro-xyphenylpyruvic acid (15), 4,4-dihydroxybiphenyl (16), 5,6-dihydroxy-indole (17), and 3,5,6-trihydroxyindole (18) were obtained in addition to melanin and from tryptophan, 5,6-dihydroxyindole (17), indole (19), anthranilic acid (20), 3-hydroxyanthranilic acid (21), indolylpyruvic acid (22), 3-hydroxypyrrol-4,5-dicarboxylic acid (23), and isatin (24). 

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