3-Hydroxyanthranilic acid oxidation

Precursors in the biosynthesis of niacin In animals and bacteria, tryptophan and in plants, glycerol and succinic acid. Intermediates in the synthesis include kynurenine, hydroxyanthranilic acid, and quinolinic acid. In animals, the niacin storage sites are liver, heart, and muscle. Niacin supplements are prepared commercially by (1) Hydrolysis of 3-cyanopyndine or (2) oxidation of nicotine, quinoltne, or collidine. 

Kynureninase is involved in the oxidative metabolism of tryptophan. It catalyzes the conversion of L-kynurenine to anthranilic acid. The enzyme also converts L-3-hydroxykyneurenine to 3-hydroxyanthranilic acid. The latter compound has a high fluorescence, which is the basis for detection in this assay. 

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. 

In independent studies, Aprison et al. (A7) found among tryptophan metabolites that 3-hydroxyanthranilic acid was capable of inhibiting the oxidation of N,N-dimethyl-p-phenylendiamine by purified ceruloplasmin and serum oxidase. 

Fig. (2). The (auto)oxidation pathway of 3-hydroxyanthranilic acid, leading to cinnabarinic acid...

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

Fig. (6). Oxidative coupling of lysine and cysteine to 3-hydroxyanthranilic acid...

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

In several instances polymeric substances arise during the transformation of secondary products, such as polymeric carbohydrates (D 1.4.1), humic acid-like polyphenols (D 3.3.1), rubber (D 6), sporopoUenins (D 6.5), polymeric products derived from 3-hydroxyanthranilic acid (D 8.4.1), melanins (D 22.1.3), lignins (D 22.2.3), and muramin (D 23.4). Many of these compounds are formed by oxidative polymerization catalyzed by phenoloxidases (C 2.3.1) and peroxidase... 

In the presence of O2, the oxidase opens the ring of 3-hydroxyanthranilate and oxidizes both the carbon bound to the hydroxyl group to yield a carboxyl group and the adjacent carbon to yield an aldehyde group. 2-Acroleyl-3-aminofumarate is the final product of the reaction. The nitrogen is then incorporated into a heterocyclic ring of quinolinic acid (or pyridine-2,3-... 

Numerous biocatalytic arene dimerizations mediated by laccases are also described. 3-Hydroxyanthranilic acid 148 is a natural substrate for oxidative dimerization by fungal laccases to give cinnabarinic acid 149, and the applicability of this transformation to other nonnatural substrates has been demonstrated (e.g., 150 to 151) [79, 80]. Crossed dimers arising from the oxidative coupling of two different hydroxyaniline substrates have also been reported [81]. Some more unusual examples of laccase-mediated oligomerizations include the oxidative dimerization/ cyclization of tyrosol 152 to give 153 [82] and the oxidative trimerization of indole 154 to give... 

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). 

Fig. 34. Formation of oxidation product of 3-hydroxyanthranilic acid by indicated amounts of enzyme and subsequent nonenzymatic conversion to quinolinic acid. ...

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

It has been observed that the metabolism of tryptophan is also greatly influenced by riboflavin deficiency. In this deficiency there is an increased excretion of metabolic products of tryptophan such as N -acetylkynurenine, N -acetyl-3-hydroxy-kynurenine, kynurenic acid, and xanthurenic acid. In a search for the specific metabolic defect Charconnet-Harding, Dalgliesh, and Neuberger Biochem. J. London) 63, 513, 1953) concluded that riboflavin might be concerned with an unknown phosphorylation step but is not concerned with the oxidative hydroxyl-ation of kynurenine to hydroxykynurenine or anthranilic acid to hydroxyanthranilic acid. The authors also point out that riboflavin may have no specific metabolic role in tryptophan metabolism. 

Several alternative pathways of L-tryptophan metabolism diverge from kynurenine (24). In mammals the quantitatively major fate of the benzene ring of the amino acid appears to be its oxidation to carbon dioxide via 3-hydroxyanthranilic acid (25), Figure 4.5. Kynurenine is first hydroxylated by a typical mixed function oxidase and the side chain is then removed, under the... 

---