Tryptophan Picolinic acid

The highly distorted octahedral complex [mer-V (pic) 3] (pic = picolinic acid, a tryptophan metabolite) oxidizes over time to the [VO(pic)2] complex in aqueous solution [39]. Conductivity measurements revealed that the species is a nonelectrolyte, and voltammetry indicated a reversible oxidation at 0.635 V and reduction at — 1.01 V versus Ag/AgCl, values which are more positive than usually observed for comparable complexes. This feature was attributed to delocalization of d electrons [39]. 

Male rats used for the perfusion experiments were maintained under established conditions and were fasted 16-24 hours prior to surgery as previously described (35). In the first series of studies the luminal perfusate was at pH 4.2. This perfusate consisted of M199 tissue culture medium which contained a variety of amino acids, vitamins and minerals plus glucose. The perfusate was supplemented (at 110 umolar) with L-histidine HCl, L-cysteine, L-methionine, L-tryptophan, 2-picolinic acid, citric acid, or reduced glutathione. The mixture was Infused into the lumen at 0.39 ml per min for 20 min and 0.10 ml per min for the final 40 min of the experiments. The small Intestine was then removed and mucosal... 

Tryptophan and Zinc Absorption Boses of 4 mg Zn and 2 mg Cu were given in Trutol to subjects consuming a diet in which tryptophan was the limiting amino acid Absorption of Zn and Cu was also measured when they received the same diet plus a picolinic acid supplement Ficolinic acid is a metabolite of tryptophan which is thought to enhance zinc absorption (17) Picolonic acid was not present in the isotope dose The diets contained 0 8-l 2 mg Cu/day and 2 7-3 6 mg Zn/day (by analysis) Total tryptophan content of the diet was approximately 250 mg/day (calculated) Ficolinic acid supplementation was at a level of 10 mg/day ... 

Table III Stable Zinc and Copper Absorption by Men Consuming a Tryptophan- Limited Diet With and Without Picolinic Acid Supplementation...

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). 

Zinc is known to provide protection against Cd and Pb toxicities (Sandstead 1980). Absorption of Zn is facilitated by complexing with picol-inic acid, a metabolite of the amino acid tryptophan. Although both Cd and Pb form complexes with picolinic acid, the resulting complexes are less stable than the Zn complex. 

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. 

Acrodermatitis enteropathica is a metabolic disorder that results in the malabsorption of zinc. However, when patients afflicted with this disorder were treated with human milk, zinc absorption was enhanced (Lombeck et al. 1975). It was reported by Evans (1980) that patients with acrodermatitis enteropathica have an impaired tryptophan metabolic pathway. Picolinic acid, a chief metabolite of tryptophan, is also a constituent of human milk. Picolinic acid is secreted by the pancreas into the intestinal lumen. A study by Boosalis et al. (1983) demonstrated that patients with pancreatic insufficiency had difficulty absorbing zinc administered as zinc sulfate. However, when these pancreatic-insufficient patients were given zinc as zinc picolinate, the extent of zinc absorption was similar to that of healthy controls. Zinc absorption may depend on the bioavailability of picolinic acid. Such a mandatory role of picolinic acid in absorption has not been confirmed (Bonewitz et al. 1982). 

The dietary requirement for nicotinamide is also related to the requirement for tryptophan. Dietary tryptophan can be converted with varying efficiencies into nicotinamide, thus dietary tryptophan spares the requirement for nicotinamide. In the domestic fowl and grain-eating birds, there is rarely an excess of tryptophan. Pyridoxal phosphate (vitamin B ) is required for the interconversion of tryptophan to nicotinamide, and so the requirements for nicotinamide are moderated by the amounts of pyridoxal and of tryptophan residues present in the diet. The ability to convert tryptophan to nicotinamide also appears to depend on the level of picolinic acid carboxylase in the liver. This enzyme converts one of the intermediates, 2-amino-3-acroleylfumaric acid into a branch path and so competes with the main pathway. The levels of this enzyme are comparatively low in the domestic fowl but are much higher in the duck, which fits with the duck having a nicotinamide requirement about double that of the domestic fowl (Scott et al., 1982). 

Most of the fluorescence in biological organisms comes from natural fluorophores such as the aromatic amino acids tryptophan, phenylalanine, and tyrosine NADH, picolinic acid, and flavins. 

The absorption of many minerals is affected by other compounds present in the intestinal lumen. As discussed in section 4.5.1, a number of reducing compounds can enhance the absorption of iron, and a number of chelating compounds enhance the absorption of other minerals. For example, zinc absorption is dependent on the secretion by the pancreas of a zinc-binding hgand (tentatively identified as the tryptophan metabolite picolinic acid). Failure to synthesize and secrete this zinc-binding ligand as a result of a genetic disease leads to the condition of acrodermatitis enteropathica— functional zinc deficiency despite an apparently adequate intake. 

Catabolite of tryptophan that is decyclized enzymatically into a semialdehyde and recyclized into quinolinic or picolinic acids or is metabolized to glutaric acid ... 

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). 

Picolinic carboxylase was discovered to undergo adaptive changes in level (336). The level is increased markedly in diabetes and other conditions leading to increased adrenal hormone secretion. This can be correlated with the depression of nicotinic acid formation from tryptophan that occurs in diabetic animals (336). The increase in picolinic acid carboxylase is dependent on the presence of adrenal hormones. 

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... 

Figure 8.4. Pathways of tryptophan metaholism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynureninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic acid 167.1. CoA, coenzyme A.

As shown in Figure 8.4, the synthesis of NAD from tryptophan involves the nonenzymic cyclization of aminocarhoxymuconic semialdehyde to quinolinic acid. The alternative metahoUc fate of aminocarhoxymuconic semialdehyde is decarboxylation, catalyzed hy picolinate carboxylase, leading into the oxidative branch of the pathway, and catabolism via acetyl coenzyme A. There is thus competition between an enzyme-catalyzed reaction that has hyperbolic, saturable kinetics, and a nonenzymic reaction thathas linear, first-order kinetics. 

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. ... 

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. 

The free nicotinamide liberated in Eq. (10a) would be converted to DPN, hence giving a net synthesis of an additional mole of DPN. It is possible that pyridine-3-aldehyde and pyridyl-3-carbinol are poor precursors of DPN in comparison to the 3-CH3-pyridine, because they may be rapidly converted to nicotinic acid at the free base stage whereas the picoline derivative is not. Tryptophan conversion to nicotinamide may also occur with intermediates at the riboside, ribonucleotide, or dinucleotide stage. That such intermediates may exist is suggested by the studies of Yanofsky i09) who has obtained evidence for the synthesis of anthranilic acid ribonucleotide in E. colt. 

Figure 2. Calibration curves for the determination of mercury with electrodes modified with tryptophan, 6-aminohexanoic acid and picolinic add.

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