Vitamin tryptophan-niacin pathway

The Tryptophan-Niacin Pathway, the Serotonin Pathway, and Vitamin Bi. 264... 

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... 

A number of inborn errors of metabolism of the tryptophan oxidative pathway (see Figure 8.4) have been reported, aU of which result in the development of pellagra that responds to high doses of niacin. These conditions include vitamin Be-responsive xanthurenic aciduria, caused by a defect of kynureni-nase (Section 9.4.3) hydroxykynureninuria, apparentiy caused by a defect of kynureninase tryptophanuria, apparentiy caused by tryptophan dioxygenase deficiency a hereditary pellagra-like condition, apparentiy caused by an increase in activity of picoUnate carboxylase and Hartnup disease. 

Hartnup disease, an autosomal recessive trait that interferes with the absorption of tryptophan, and carcinoid syndrome in which the amino acid is preferentially oxidized to 5-hydroxytryptophan and serotonin. Prolonged treatment with the drug isoniazid, which competes with pyridoxal 5 -phosphate (a vitamin Be-derived coenzyme required in the tryptophan-to-niacin pathway), also reduces the conversion of tryptophan to niacin. Oral contraceptives that contain high doses of estrogen increase tryptophan conversion efficiency (Braidman and Rose 1971). 

Certain vitamins can be synthesized by humans in limited quantities. Niacin can be formed from tryptophan (Chapter 17). This pathway is not active enough to satisfy all the body s needs however, in calculating the RDA for niacin, 60 mg of dietary tryptophan is considered equivalent to 1 mg of dietary niacin. In Hartnup s disease (see Table 38-1 and Chapter 17), a rare hereditary disorder in the transport of monoaminomonocarboxylic acids (e.g., tryptophan), a pellagra-like rash may appear, suggesting that over a long period of time dietary intake of niacin is insufficient for metabolic needs. This pattern also occurs in carcinoid syndrome in which much tryptophan is shunted into the synthesis of 5-hydroxytryptamine. 

If the dietary levels of niacin and tryptophan are insufficient, the condition known as pellagra results. The symptoms of pellagra are dermatitis, diarrhea, dementia, and, finally, death. In addition, abnormal metabolism of tryptophan occurs in a vitamin B6 deficiency. Kynurenine intermediates in tryptophan degradation cannot be cleaved because kynureninase requires PLP derived from vitamin B6. Consequently, these intermediates enter a minor pathway for tryptophan metabolism that produces xanthurenic acid, which is excreted in the urine. 

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. 

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