5- picolinic acid, metabolism

In humans and animals, chromium(III) is an essential nutrient that plays a role in glucose, fat, and protein metabolism by potentiating action of insulin. Chromium picolinate, a trivalent form of chromium complexed with picolinic acid, is used as a dietary supplement, because it is claimed to speed metabolism... 

IPC is also effective for pharmacology related to brain disease. It was used to analyze picolinic acid and related compounds [90], neurotoxins associated with paralytic shellfish poisoning [91], a drug candidate for treating Alzheimer s disease [92], and nicergoline, clinically used for improving brain metabolism [93]. Quaternary ammonium anticholinergics were determined in whole blood and the matrix effect was taken into account [94]. 

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). 

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). 

Picolinic Add Metabolism. Picolinic acid is converted to its glycine conjugate when administered to mammals. - Birds use ornithine in place of glycine. The mechanism of the condensation is not known, but presumably it resembles the formation of hippuric acid, in which a CoA derivative of the carboxyl group is the acylating agent. A-Methylpicolinic... 

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). 

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 metabolism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynttreninase, 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 add 167.1. CoA, coenzyme A...

Cr(III) is held to be essential for human and animal nutrition, necessary for the maintenance of glucose, lipid, and protein metabolism, and is therefore used as a dietary supplement mostly in the form of its picolinate or nicotinate. Trivalent chromium is poorly absorbed principally because, unless heavily com-plexed, it will precipitate under most physiological pH conditions. Whilst Cr(III) compounds appear to be able to produce genetic effects with purified nucleic acids or cell nuclei, there is generally no such activity in intact cellular systems due to the relatively poor ability of Cr(III) to cross cell membranes. 

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. 

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). 

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