Anthranilic acid metabolism

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... 

Cinnamyl anthranilate is metabolized by hydrolysis to anthranilic acid and cinnamyl alcohol, which is oxidized to benzoic acid. In mice, but not in rats or humans, the hydrolysis is saturated at high doses, leading to excretion of unchanged cinnamyl anthranilate in the urine. 

Cinnamyl anthranilate has the characteristic effects of a peroxisome proliferator on mouse liver, increasing the activity of peroxisomal fatty acid-metabolizing enzymes and microsomal CYP4A and increasing hepatocellular proliferation. These effects are mediated by the intact ester, and were not seen after administration of the hydrolysis products, cinnamyl alcohol and anthranilic acid. The corresponding effects on rat liver were very much weaker. No relevant data from humans were available. 

Little information is available regarding tissue distribution or metabolic products of nonsteroidal anti-inflammatory drugs in cattle. The early synthetic compounds were simple derivatives either of salicylic acid such as acetylsalicylic acid and methylsalicylic acid, or of pyrazolone such as metamizole, oxyphenbuta-zone, phenylbutazone, propylphenazone, and suxibuzone. Modern nonsteroidal anti-inflammatory drugs are derivatives either of anthranilic acid such as dido-... 

Tolfenamic acid is used as an injectable formulation in cattle and swine. In rats and target animals, tolfenamic acid is metabolized by hydroxylation either of the methyl or the methylchlorophenyl group producing two metabolites further oxidation of the hydroxymethyl group to the corresponding aldehyde or carboxylic acid can produce two additional metabolites. The two hydroxylated metabolites of tolfenamic acid, N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid, are much less potent than the parent compound in terms of anti-inflammatory and analgesic... 

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. 

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.

Various reports in the literature indicate the influence of endocrine organs on tryptophan metabolism. Chiancone and co-workers (C5, V2) reported that ovariectomy or hypophysectomy of rats caused increased excretion of xanthurenic acid and that adrenalectomy caused a decrease. An adrenal mechanism is suggested for the regulation of 3-hydroxy-anthranilic acid conversion to nicotinic and picolinic acids (M7). 

In view of the hypoglycemic and insulinase-inhibitory action of l-tryptophan, it seemed pertinent to Mirsky to study the effect of various metabolic products of tryptophan on the blood sugar of normal and diabetic rats (M9), A statistically significant hypoglycemic response was produced after oral administration of anthranilic acid, niacin, indole-3-acetic acid, 5-hydroxytryptophan, and serotonin. A hypoglycemic fol-... 

Meclofenamic acid is an anthranilic acid derivative that is typically administered orally to horses. The pharmacokinetics of this NSAID in horses has been well defined. For example, the plasma half-life in horses has been determined in several studies and varies between 0.7 and 1.4 h (Johansson et al 1991, Snow et al 1981). Absorption is variable after oral dosing with estimates of bioavailability ranging from 60 to 90% and peak plasma concentrations occurring 1-3 h after administration (Johansson et al 1991). The effect of ingesta on the absorption of meclofenamic acid from the gastrointestinal tract has not been determined definitively. In one study, the absorption rate of the NSAID was the same in ponies whether they were fasted or fed (Snow et al 1981). However, another study found that absorption of meclofenamic acid was delayed in horses allowed free access to hay (May Lees 1999). In horses, the liver metabolizes meclofenamic acid primarily by oxidation to an active hydroxymethyl metabolite, which may be further oxidized to an inactive carboxyl metabolite (Plumb 1999). 

Fujigaki, S., Saito, K., Takemura, M., Fujii, H., Wada, H., Noma, A., and Seish-ima, M., Species differences in L-tryptophan-kynurenine pathway metabolism Quantification of anthranilic acid and its related enzymes, Arch. Biochem. Biophys., 358, 329, 1998. 

The third kind of hydroxylase activity is the only one pertinent to the present review and refers to a mono-oxygenase of the hydroxylase type. This catalyses the insertion of a -OH group in place of a hydrogen atom at the 3-position of anthranilic acid, leading to HA. This evenience is often simply ignored by many authors dealing with tryptophan metabolism, so it could seem that the only possibility of HA formation is the action of kynureninase on HK. The actual occurrence of a true hydroxylase, as defined above, could however be considered debatable for a number of reasons, but some authors merely notice the activity without giving any reference to it. 

However, a more recent study exists [33], also based on the use of isotopically labeled anthranilic acid, which demonstrated that the substance is unable to increase HA levels in the liver and in the urines, when administered to rats on the contrary, such an increase was observed when either kynurenine or HA were administered, suggesting that the pathway, operating in mammals, should be kynurenine - HK - HA, and not kynurenine - anthranilic acid - HA. In that study, it was also concluded that the preferred route of kynurenine further metabolism was through... 

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]. 

Fic. 1. Metabolism of tryptophan to serotonin (5-hydroxytryptamine) and niacin. Fyiidoxal phosphate (PLP) dependent reactions are indicated. Reactions not shown which may result in formation of products excreted in urine include the acetylation of liymuenine and 3-hydroxykynurenine, conjugation of anthranilic acid with glycine (to form o-aminohippuric acid) and with glucuronic acid, and the dehydroxylation of kynurenic acid and xanthurenic add to quinaldic add and 8-hydroxyquinaldic add, respectively. 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid, and 1-deoxyxylulose 5-phosphate (Figure 2.1). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate, and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthranilic acid as aromatized CoA ester, anthraniloyl-CoA). Shikimic acid is a product of the glycol5dic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyr-uvate and erythrose 4-phosphate (Figure 2.1). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline, and acridine. 

Because shikimic acid does not enter into mammalian metabolism, its synthesis and use are clear targets at which to aim selective toxicity. In bacteria, shikimic acid arises by cyclization of the carbohydrate 3-deoxy-2-oxo-D- mAzVzoheptulosonic acid 7-phosphate, which is formed by the condensation of erythrose 4-phosphate and phosphoenolpyruvic acid. Shikimic acid undergoes biosynthesis to chorismic acid (4.55) which is the enolpyruvic ether of raw5-3,4-dihydroxy cyclohexa-1,5-diene-1-carboxylic acid. As its name indicates, this acid sits at a metabolic fork, the branches of which lead to prephenic acid, to phenylalanine (and hence to tyrosine), to anthranilic acid (and hence tryptophan), to ubiquinone, vitamin K, and/ -aminobenzoic acid (and hence folic acid). 

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