Nicotinic Tryptophan metabolism

B19. Banerjee, S., and Agarival, P. S., Nicotinic acid-tryptophan metabolism in certain diseases. Proc. Soc. Exptl. Biol. Med. 97, 65-68 (1958). 

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). 

The peculiarities of tryptophan metabolism in the 15 individual members of this family were demonstrated by oral ingestion of 10 g DL-tryp-tophan per test case and quantitative determination of the urinary content of kynurenine, 3-hydroxykynurenine, xanthurenic acid, nicotinic acid amide and its N -methyl derivative, and 4-pyridoxic acid. Of the 15 members of the family examined 6 showed, repeatedly, abnormal levels of... 

P5. Piazza, M., and Tancredi, F., Tryptophan-nicotinic acid metabolism in subjects recently or long since recovered from viral hepatitis. Nature 197, 903 (1963). 

Ql. Quagliariello, E., Tancredi, F., Fedele, L., and Saccone, C., Tryptophan-nicotinic acid metabolism in patients with tumors of the bladder. Changes in the excretory products after treatment with nicotinamide and vitamin Bg. Brit. J. Gancer 15, 367-371 (1961). 

In 1945 Elvehjem and co-workers (518) reported that nicotinic acid-deficient rats would grow if given tryptophan, suggesting conversion of tryptophan to nicotinic acid. Hosen and co-workers (731) showed that administration of tryptophan to rats increased the urinary excretion of nicotinic acid derivatives, and numerous workers confirmed the conversion of tryptophan to nicotinic acid in man (399, 667, 755) and many other species (summary, 820). In the last ten years there has been intensive investigation of tryptophan metabolism. 

By 1950 the outline of the main pathway for tryptophan metabolism was therefore established, and it was becoming apparent that the over-all conversion of tryptophan to nicotinic acid was markedly reduced in many B-vitamin deficiencies. Thus this occurred in pyridoxine deficiency (50, 387, 732, 784), riboflavin deficiency (387,455, 675), and thiamine deficiencj (455, 675) but not in pantothenate or folic acid deficiencies (455). 

The pyridine nucleotides are the functional form of nicotinic acid, but still comparatively little work has been done on their relation to tryptophan-nicotinic acid metabolism. Two possibilities must be considered the pyridine nucleotides may be formed from tryptophan without intermediacy of nicotinic acid and only give nicotinic acid on breakdown, or nicotinic acid first formed from tryptophan may be incorporated into pyridine nucleotides. The latter now seems the more likely possibility, though the former has not been excluded. 

In the greater part of the preceding discussion nicotinic acid has, for brevity, been treated as the end product of tryptophan metabolism. In fact the end products consist of several metabolites of nicotinic acid, which can... 

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. 

Tryptophan is an essential amino acid which is ingested by Americans in quantities that exceed the normal daily requirements for protein synthesis (Rl), and considerable amounts are converted to nonprotein substances such as nicotinic acid and serotonin (Fig. 1). The tryptophan-niacin pathway, which is also known as the kynurenine pathway (Fig. 1), is important for production of the vitamin, nicotinic acid, and provides also a means for degrading tryptophan to acetoacetyl-CoA, carbon dioxide, and ammonia (P7). The amount of tryptophan metabolized by the various pathways available depends greatly on the amount of... 

Tenconi LT, Acocella G (1966) Study on the Chemotherapy of Experimental Lead Poisoning. 1. Effects of Lead Poisoning on the Tryptophan to Nicotinic Acid Metabolism in the Rat. Acta Vitaminologica 20 189... 

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. ... 

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... 

A number of drugs that react with carbonyl compounds are capable of causing vitamin Bg deficiency on prolonged use. These include the antituberculosis drug isoniazid (iso-nicotinic acid hydrazide), penicillamine, and the anti-Parkinsonian drugs, benser-azide and carbidopa. In general, the main effect is impairment of tryptophan metabolism by inhibition of kynureninase, and hence the development of the niacin-deficiency disease, pellagra. The condition therefore responds to the administration of either vitamin Bg or niacin. 

Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions (Figure 45-11). About 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as mg niacin equivalents = mg preformed niacin + 1/60 X mg tryptophan. Because most of the niacin in cereals is biologically unavailable, this is discounted. 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

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... 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

Nicotinate and nicotinamide, together referred to as niacin, are required for biosynthesis of the coenzymes nicotinamide adenine dinucleotide (NAD"") and nicotinamide adenine dinucleotide phosphate (NADP" ). These both serve in energy and nutrient metabolism as carriers of hydride ions (see pp. 32, 104). The animal organism is able to convert tryptophan into nicotinate, but only with a poor yield. Vitamin deficiency therefore only occurs when nicotinate, nicotinamide, and tryptophan are all simultaneously are lacking in the diet. It manifests in the form of skin damage (pellagra), digestive disturbances, and depression. 

Niacin is also known as vitamin PP or vitamin Bj. The term niacin describes two related compounds, nicotinic acid and nicotinamide (Figure 19.18), both with biological activity. Niacin is formed from the metabolism of tryptophan, and therefore it is not strictly a vitamin. It is a precursor of two cofactors nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for the functioning of a wide range of enzymes involved in redox reactions. 

Niacin is a generic term which refers to two related chemical compounds, nicotinic acid (6.22) and its amide, nicotinamide (6.23) both are derivatives of pyridine. Nicotinic acid is synthesized chemically and can be easily converted to the amide in which form it is found in the body. Niacin is obtained from food or can be synthesized from tryptophan (60 mg of dietary tryptophan has the same metabolic effect as 1 mg niacin). Niacin forms part of two important co-enzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are co-factors for many enzymes that participate in various metabolic pathways and function in electron transport. 

Niacin is found in unrefined and enriched grains and cereal, milk, aid lean meats, especially liver. Limited quantities of niacin can also be obtained from the metabolism of tryptophan. [Note The pathway is inefficient in that only about 1 mg of nicotinic acid is formed from 60 mg of tryptophan. Further, tryptophan is metabolized to niacin orty when there is a relative abundance of the amino acid—that is, alter the needs for protein synthesis and energy production have been met]... 

Tryptophan is a metabolic precursor for many important biochemical compounds, such as nicotinic acid, kynurenic acid, serotonin, and melatonin (67). The tryptophan content of various food-... 

McCreanor CM and Bender DA (1986) The metabolism of high intakes of tryptophan, nicotinamide and nicotinic acid in the rat. British Journal of Nutrition 56, 577-86. 

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