Quinolinic acid, from tryptophan metabolism

The synthesis of NAD from tryptophan involves the non-enzymic cyclization of aminocarboxymuconic semialdehyde to quinolinic acid. The alternative metabolic fate of aminocarboxymuconic semialdehyde is decarboxylation, catalysed by picolinate carboxylase, leading to acetyl CoA and total oxidation. There is thus competition between an enzyme-catalysed reaction, which has hyperbolic, saturable kinetics, and a non-enzymic reaction, which has linear kinetics. At low rates of flux through the pathway, most metabolism will be by way of the enzyme-catalysed pathway, leading to oxidation. As the rate of formation of aminocarboxymuconic semialdehyde increases, and picolinate carboxylase becomes more or less saturated, so an increasing proportion will be available to undergo cyclization to quinolinic acid and onward metabolism to NAD. There is thus not a simple stoichiometric relationship between tryptophan and niacin, and the equivalence of the two coenzyme precursors will vary as the amount of tryptophan to be metabolized and the rate of metabolism vary. 

This intermediate appears to be important in the formation of a number of pyridinecarboxylic acids. Figure 2 depicts the formation of quinolinic acid from compound 1. Quinolinic acid formation is a spontaneous reaction and does not reqmre enzymes. Only one of several Neurospora mutants can use quinolinic acid in place of nicotinic acid, and in this mutant the activity is very low. Quinolinic acid is also a very poor growth factor. The dicarboxylic acid appears to be a by-product of tryptophan metabolism and not an intermediate in nicotinic acid formation. Although quinolinic... 

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... 

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metaboUte quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normal conditions, almost aU of the dietary intake of tryptophan, apart from the small amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is by way of 5-hydroxylation and decarboxylation to 5-hydroxytryptarnine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

The second quinoline derivative produced in animal metabolism is xanthurenic acid, which was isolated by Musajo (M12). Xanthurenic acid (4,8-dihydroxyquinoline-2-carboxylic acid) also originates from tryptophan through kynurenine (M13). 

This chapter discusses the pathways by which L-tryptophan is metabolized into a variety of metabolites, many of which have important physiological functions. A few metabolites are cited here briefly. Quinolinic acid is involved in the regulation of gluconeogenesis. Picolinic acid is involved in normal intestinal absorption of zinc. The body s pool of nicotinamide adenine dinucleotide (NAD) is influenced by L-tryptophan s metabolic conversion to niacin. Finally, L-tryptophan is the precursor of several neuroactive compounds, the most important of which is serotonin (5-HT), which participates as a neurochemical substrate for a variety of normal behavioral and neuroendocrine functions. Serotonin derived from L-tryptophan allows it to become involved in behavioral effects, reflecting altered central nervous system function under conditions that alter tryptophan nutrition and metabolism. 

The increased plasma kynuremne pool and the induced xanthurenic acid urinary excretion have several implications in the assessment of diazinon noncholinergic toxicity. An increase in xanthurenic acid formation may alter glucose metabolism. Xanthurenic acid has been reported to form a complex with insulin and damage pancreatic P cells. Elevated plasma kynurenin may alter kynurenin transport into the brain. Since more than 40% of brain kynurenin originates from the systemic circulation, cerebral biosynthesis of neuroactive kynurenin metabolites such as quinolinic acid and kynurenic acid may change. Finally, the availability of L-iryptophan for other L-lryptophan-dependent processes may be reduced. Tryptophan is the metabolic precursor for. serotonin and nicotinic adenine dinucleotidc. Diabetes, bladder cancer, and neurological disorders may be the toxic consequences of diazinon-altered L-tryptophan metaboli.sm (Seifert and Pewnim, 1992 Pewnim and Seifert, 1993). 

It might be anticipated that Be deficiency would result in deficient pyridine nucleotide synthesis, since 3-hydroxykynureninase is sensitive to PLP depletion. Studies of nutritional B deficiency in man, however, indicate that, although tryptophan metabolism becomes abnormal, urinary output of quinolinic acid still increases after a tryptophan load (R15). Decreased formation of pyridine nucleotides from tryptophan may occur only when PLP depletion is severe (R15). 

Kynurenine Metaholism. Kynurenine may be metabolized in five ways acetylation to iV -acetylkynurenine,i decarboxylation to kynuramine, oxidation to 3-hydroxykynurenine, cyclization to a quinoline derivative, and cleavage to yield anthranilic acid." The oxidation, cyclization, and cleavage reactions are components of major pathways of tryptophan metabolism. Ommochrome is composed of a series of heterocyclic condensed ring systems that have been shown to be derived from tryptophan via kynurenine. The individual steps in the enzymatic formation of the pigments have not separated. ... 

As shown in Figure 11.13, the nicotinamide nucleotide coenzymes can be synthesized from either of the niacin vitamers, and from quinolinic acid, an intermediate in the metabolism of tryptophan. In the liver, the oxidation of tryptophan results in a considerably greater synthesis of NAD than is required, and this is catabolized to release nicotinic acid and nicotinamide, which are taken up and used by other tissues for synthesis of the coenzymes. 

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