3-Hydroxyanthranilic acid metabolism

Bokman AH, Schweigert BS (1951) 3-Hydroxyanthranilic acid metabolism. IV. Spectropho-tometric evi-dence for the formation of an intermediate. Arch Biochem Biophys 33 270-276... 

Moline, S.W., Walker, H.C., Schweigert, B.S. 3-Hydroxyanthranilic acid metabolism. VII. Mechanism of formation of quinolinic acid. J. biol. Chem. 234, 880-883 (1959)... 

Cain RB (1968) Anthranilic acid metabolism by microorganisms. Formation of 5-hydroxyanthranilate as an intermediate in anthranilate metabolism by Nocardia opaca. Anthonie van Leewenhoek 34 417-432. 

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... 

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. 

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. 

Chizhova and Ivanova (C7) studied 20 children, aged 1-12 years, under therapy for leukemia and 10 healthy children as control. A total of 15-20 g of tryptophan was administered during 5-10 days (1.5-3 g/day) to 7 children whereas 13 were given a single dose of 2-3 g. Daily determinations of urinary metabolites by paper chromatography demonstrated a disturbance of tryptophan metabolism in 19 of the 20 leukemic children before and after tryptophan loading. Kynurenine, 3-hydroxykynurenine, and anthranilic and 3-hydroxyanthranilic acids appeared in urine, whereas 5-hydroxyindoleacetic acid was absent in the majority of the young patients. The disturbances of tryptophan metabolism were similar in all of them. Administration of vitamin Be restored tryptophan metabolism to normal in the majority of the patients. 

B17. Boyland, E., and Watson, G., 3-Hydroxyanthranilic acid, a carcinogen produced by endogenous metabolism. Nature 177, 837-838 (1956). 

In addition many stages in knowm pathways of tryptophan metabolism require further investigation, in particular, the intermediate lying between tryptophan and formylkynurenine, the hydroxylation reaction in conversion of kynureine to hydroxykynurenine, the intermediates in the conversion of hydroxyanthranilic acid to nicotinic acid, and the site of synthesis and hormonal function of 5-hydrox3dryptamine. 

Kyrmreninase (EC 3.7.1.3). Failure to convert 3-hy-droxykynurenine to 3-hydroxyanthranilic acid, and kynurenine to anthranilic acid. Increased urinary xanthurenic acid, kynurenine and 3-hydroxykynurenine, especially after ingestion of tryptophan. Some patients mentally retarded, others symptomless. Enzyme may not be absent, but structurally abnormal, with decreased affinity for coenzyme (dietary vitamin Bj temporarily corrects metabolic disturbance, and addition of pyridoxal phosphate to liver biopsy material increases enzyme activity to near normal). See Tryptophan. 

Certain microorganisms degrade L-tryptophan (in some cases also D-trypto-phan) via kynurenic acid to compounds of primary metabolism (Fig. 265, quinolinic pathway of tryptophan degradation, in contrast to the aromatic pathway via 3-hydroxyanthranilic acid shown in Fig. 244). 

Kynurenine is hydroxylated to hydroxykynurenine by an enzyme (kynurenine-3-hydroxylase) found in rat liver mitochondria. The reaction requires NADPH and molecular oxygen. In the presence of pyridoxal phosphate, hydroxykynurenine is hydrolyzed by an enzyme (kynurenase) found in liver and kidney. The product of this reaction is 3-hydroxyanthranilic acid. The same enzyme catalyzes the cleavage of the side chain of kynurenine to yield alanine and anthranilic acid. Studies made with labeled 3-hydroxyanthranilic acid demonstrated its role as an intermediate of the biosynthesis of nicotinic acid. These studies established that the label of the carbon 3 of 3-hydroxyanthranilic acid is transferred to the a-carbon of quinolinic acid and is lost as C14O2 during the conversion of quinolinic to nicotinic acid. The details of the metabolic conversion of 3-hydroxyanthranilic acid to nicotinic acid are known. 

Henderson, L.M., and Ramasarma, G.B., 1949. Quinolinic acid metabolism. III. Formation from 3-hydroxyanthranilic acid by rat liver preparations. Journal of Biological Chemistry. 181 687-692. 

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. 

Figure 2 NAD metabolism. Tip = tryptophan, 3-HK = 3-hydroxykynurenine, 3-HA = 3-hydroxyanthranilic acid, ACMS = a-amino-P-carboxymuconate- -semialdehyde, AMS = a-aminomuconate- -semialdehyde, NaMN = nicotinic acid mononucleotide, NMN = nicotinamide mononucleotide, NaAD = nicotinic acid adenine dinucleotide. For other abbreviations, see Figure 1. (1) tryptophan oxygenase [EC 1.13.11.11], (2) formy-dase [EC 3.5.1.9], (3) kynurenine 3-hydroxylase [EC 1.14.13.9], (4) kynureninase [EC 3.7.1.3], (5) 3-hydroxyanthranilic acid oxygenase [EC 1.13.11.6], (6) nonenzymatic, (7) aminocarboxymuconate-semialdehyde decarboxylase [EC 4.1.1.45], (8) quinolinate phos-phoribosyltransferase [EC 2.4.2.19], (9) NaMN adenylyltransferase [EC 2.7.2.18], (10) NAD synthetase [EC 6.3.5.1], (11) NAD kinase [EC 2.7.1.23], (12) NAD" glycohydro-lase [EC 3.2.2.5], (13) nicotinamide methyltransferase [EC 2.2.1.1], (14) 2-Py-forming MNA oxidase [EC 1.2.3.1], (15) 4-Py-forming MNA oxidase [EC number not given], (16) nicotinamide phosphoribosyltransferase [EC 2.4.2.12], (17) NMN adenylytransferase [EC 2.7.71], (18) nicotinate phosphoribosyltransferase [EC 2.4.2.11], (19) nicotinate methyltransferase [EC 2.7.1.7], and nicotinamidase [EC 3.5.1.19]. Solid line, biosynthesis dotted line, catabolism.

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... 

Y. Nishizuka, A. Ichiyama, R. K. Gholson, and O. Hayaishi, Studies on the metabolism of the benzene ring of tryptophan in mammalian tissues. I. Enzymic formation of glutaric acid from 3-hydroxyanthranilic acid, / Biol. Chem. 240, 733-739 (1965). 

The outcome of the different lines of investigation is that a number of pathways of tryptophan metabolism have been established. In the vertebrate organism the two well-known pathways are the kynurenine-hydroxyanthranilic acid and the serotonin pathways. Studies with Pseudomonas bacteria led Stanier and Hayaishi (876) to propose two pathways for the dissimilation of the products of tryptophan metabolism starting at the level of kynurenine. One of these is through anthranilic acid and catechol, referred to as the aromatic pathway, and the other through kynurenic acid, named the quinoline pathway. 

Cleavage of the benzene ring of the hydroxyanthranilic acid moiety and conversion of the intermediate to nicotinic acid, picolinic acid, and quinolinic acid are very important steps in the metabolism of tryptophan. In addition to the formation of the above compounds, ring cleavage is part of the probable pathway for the complete oxidation of the hydroxyanthranilic acid to CO2 in vertebrates (323). 

Hydroxyanthranilate oxidase functions during intermediary metabolism of tiyptophan, as depicted in Figure 4. It transforms 3-hydroxyanthranilic acid into a substance, not raitirely characterized, from which quinolinic, picolinic, and nicotinic adds arise (75,76, 188,346,348,449,540,649,650,776,833, and the reviews 182,312,538). The enzyme occurs in pig, ox and rat liver and kidney, but not in other organs (348,600,650,666). 

These studies were confirmed by tracer experiments showing that nitrogen of nicotinic acid (formed by Neurospora) is derived from 3-hydroxyanthranilic acid (478). Experiments with doubly labeled tryptophan demonstrate that tryptophan is probably the only source of quinolinic acid in rat metabolism (645) and that carbon atom 3 of tryptophan, the precursor of the carboxyl carbon of 3-hydroxyanthranilic acid, becomes carboxyl carbon in nicotinic acid (310,340,341,373). In vitro studies of the enzymic oxidation of 3-hydroxyanthranilic acid confirm its relationship to quinolinic acid (498) and show that picolinic acid may also form from it (539,540) but nicotinic acid synthesis under... 

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