Nicotinic acid tryptophan, conversion

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. 

Drug-induced niacin deficiency has resulted from the use of isonicotinic acid hydrazide, which interferes with the conversion of niacin from tryptophan. Administration of ethanol or the antimetabolites 6-mercaptop-urine and 5-fluorouracil also may lead to niacin deficiency. The uricosuric effects of sulfinpyrazone and probenecid may be inhibited by nicotinic acid. 

It was furthermore reported (K20) that nicotinic acid-deficient animals would grow only if given tryptophan, thus suggesting the conversion of tryptophan to nicotinic acid. Not only is tryptophan converted to nicotinic acid but also kynurenine and 3-hydroxyanthranilic acid. The peculiar degradation of the latter to pyridine derivatives gave rise to many interesting investigations. 3-Hydroxyanthranilic acid is derived from 3-hydroxykynurenine, another important tryptophan metabolite, the his-... 

P13. Prinsloo, J. G., Joubert, C. P., de Lange, D. J., du Plessis, J. P., and Hojby, T., The conversion of tryptophan to nicotinic acid in South African Bantu pellagrins with special reference to the role of pyridoxine and riboflavine. Proc. Nutr. Soc. S. Africa 3, 66-71 (1962) Ghem. Abstr. 60, 16265 (1964). 

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. 

It was quickly established by many techniques (381, 430, 782, 817, 957, and review 170) that the conversion of tryptophan to nicotinic acid occurred in body tissues and was not due (except perhaps in part in exceptional circumstances cf. 170) to intestinal bacteria. Moreover nutritional studies showed that kynurenine was probably also a precursor of nicotinic acid (457) and that kynurenine and xanthurenic acid excretion were increased in pyridoxine deficiency (21). 

Interest then moved to animals. Both isotopic and nutritional experiments showed that the pathway established in microorganisms applied equally to mammals. Thus hydroxyanthranilic acid was converted to nicotinic acid (9, 604), which it could replace as a growth factor (944), whereas there was no similar conversion of anthranilic acid (343). An outstanding series of isotopic experiments, especially by Heidelberger and co-workers, showed that the 8-carbon atom of the tryptophan side chain became the 8-carbon atom of the kynurenine side chain and that the side chain was lost in conversion of kynurenine to nicotinic acid (369, 371, 427). Moreover the carbon in the 3-position of the indole nucleus became the carboxyl carbon of nicotinic acid (370 this experiment proved conclusively the reality of the tryptophan-nicotinic acid conversion) and the indole nitrogen appeared with only slight dilution in kynurenine, kynurenic acid, and xanthurenic acid (759). All these relations are those to be expected for the pathway tryptophan —+ kynurenine —> hydroxykynurenine (or its phosphate) —> hydroxyanthranilic acid (or its phosphate) — nicotinic acid, illustrated in diagrams 17 and 18. 

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). 

No cofactors have been reported in the tryptophan peroxidase-oxidase reaction, but the marked reduction in the conversion of tryptophan to nicotinic acid in thiamine deficiency has been found in all probability to be due to interference with the reaction at the tryptophan peroxidase-oxidase stage (173 c/. diagram 19). The evidence is still inadequate to show how enzyme function and vitamin are related. Biotin may also be concerned in the reaction (800 but see 175a). 

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 involved in synthesis of several important compounds. Nicotinic acid (amide), a vitamin required in the synthesis of NAD+ and NADP+, can be synthesized from tryptophan (Figure 17-24). About 60 mg of tryptophan can give rise to 1 mg of nicotinamide. The synthesis begins with conversion of tryptophan to N-formylkynurenine by tryptophan pyrrolase, an inducible iron-porphyrin enzyme of liver. N-Formylkynurenine is converted to kynurenine by removal of formate, which enters the one-carbon pool. Kynurenine is hydroxylated to 3-hydroxykynurenine, which is converted to 3-hydroxyanthranilate, catalyzed by kynureninase, a pyridoxal phosphate-dependent enzyme. 3-Hydroxyanthranilate is then converted by a series of reactions to nicotinamide ribotide, the immedi-... 

Georg, L. K. Conversion of tryptophan to nicotinic acid by Trichophyton... 

Ribose phosphates phosphorylated derivatives of ribose. Ribose is phosphorylated in position 5 by the action of ribokinase (EC 2.7.1.15) and ATP ribose 5-phosphate is also produced in the Pentose phosphate cycle (see), and in the Calvin c cle (see) of photosynthesis. Phosphoribomutase cat yses the interconversion of ribose 5-phospbate and ribose 1-phosphate, and the cosubstrate of this reaction is ribose l,5-f>isphosphate. 5-Phosphoribosyl 1-pyrophos-phate donates a ribose 5-phosphate moiety in the de novo biosynthesis of purine and pyrimidine nucleotides (see Purine biosynthesis. Pyrimidine biosynthesis), in the Salvage pathway (see) of purine and pyrimidine utilization, in the biosynthesis of L-Histi-dine (see) and L-Tryptophan (see) and in the conversion of nicotinic acid into nicotinic acid ribotide (see Pyridine nucleotide cycle). Ribose 1-phosphate can also take part in nucleotide synthesis (see Salvage pathway). 

The conversion of tryptophan into nicotinic acid involves a series of molecular transformations. The original tryptophan molecule not only loses its alanine side chain and its imidazole ring, but it also includes nitrogen in its benzoic ring to form a pyridine ring [69-71]. 

Quinolinate decarboxylation and conversion to nicotinic acid mononucleotide is catalysed by quinolinate phosphoribosyltransferase, a rate-limiting enzyme in the conversion of tryptophan to NAD the reaction requires Mg and is negatively regulated by nicotinamide. Next the transfer of adenylate from ATP by an intermediate of nicotinamide/nicotinate-mononucleotide-adenyl-transferases isoenzymes (NMNAT, see below) yields nicotinic acid adenine... 

Among the most interesting of the biological reactions of tryptophan is its conversion to nicotinic acid. In the vertebrates, at any rate, this is a truly anabolic process which serves the end of providing source material for the synthesis of DPN and TPN. The discussion of this pathway of metabolism is contained in the chapter. Synthetic Processes Involving Amino Acids. Conversion to nicotinic acid can not be the major pathway for the catabolism of tryptophan. Based on the capacity of fed tryptophan to prevent symptoms of niacin deficiency in animals, it can be calculated that only 1% or 2% is thus converted in man and the primates. In the rat the conversion may amount to as much as 10%. 

There is abundant evidence that kynurenic and xanthurenic acids are not intermediates in the formation of nicotinic acid. In experiments with tryptophan labeled with C in the /3-position of the side chain it was found that the alanyl side chain of tryptophan is lost during its conversion to nicotinic acid. The same result was obtained with tryptophan labeled with C in the carboxyl group. 

Fi(i. 8. Scheme of the probable pathway of the conversion of tryptophan to nicotinic acid. 

Pyridoxine deficiency in the diet causes disorders in protein metabolism, e. g., in hemoglobin synthesis. Hydroxykynurenine and xanthurenic acid accumulate, since the conversion of tryptophan to nicotinic acid, a step regulated by the kynureni-nase enzyme, is interrupted. 

This is the excretion product of 3-hydroxykynurenic acid, an intermediate in the conversion of tryptophan to nicotinic acid. Pyridoxal phosphate is required as a cofactor for the enzyme, kynureninase, which catalyses the conversion of 3-hydroxykynurenic acid to 3-hydroxyanthrinilic acid. In patients with pyridoxine deficiency, 3-hydroxykynurenic acid accumulates and is excreted in the urine as xanthurenic acid. Xanthurenic acid can therefore be measured in urine (especially after giving an oral typtophan load) in order to detect pyridoxine deficiency. 

Tryptophan conversion to niacin (nicotinic acid). It assists in forming niacin (nicotinic acid) from tryptophan, thereby playing a role in the niacin supply. 

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). 

Neurovpora craasa can readQy convert tryptophan to nicotinic acid. This has been established by the classic use of mutants, and with these mutants most of the intermediates in the tryptophan-niacin conversion were obtained (see below). Davis a al (IS) showed that the bacterium XarUhomonas pruni could utilize tryptophan instead of niacin. Other bacteria, however, such as Escherichia coli and Bacillus subtUis, do not show a tryptophan-niacin relationship (14, IS). Kidder et al. (16) were also unable to demonstrate this relationship in Tetrahymena. 

Tryptophan oxidation in liver has been found to be adaptive (36,43,44)-Administration of the amino acid to rabbits or rats results in an approximately tenfold increase in the amount of the tryptophan oxidizing system. This rise in enzyme occurs some 6 hr after the administration of a single dose of tryptophan, and then rapidly decreases. This increase appears to be due to true synthesis, since ethionine will inhibit the adaptive formation of the enzyme (46). It is of interest that the only step in the conversion of tryptophan to nicotinic acid which is adaptive is the oxidation to formyl-kynurenine (43),. This is in contrast to the finding in bacteria, where a number of the enzymes in the tryptophan oxidation sequence have been found to be adaptive (43). 

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. 

The conversion of tryptophan to nicotinic acid in vivo is depicted in Figure 1. The rate of conversion of tryptophan to niacin and the pyridine nucleotides is controlled by the activities of tryptophan dioxygenase (known alternatively as tryptophan pyrrolase), kynurenine hydroxylase, and kynureninase. These enzymes are, in turn, dependent on factors such as other B vitamins, glucagon, glucocorticoid hormones, and estrogen metabolites, and there are various competing pathways which also affect the rate of conversion. For these reasons, a variety of nutrient deficiencies, toxins, genetic and metabolic abnormalities, etc. can influence niacin status and requirements. 

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). 

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