Tryptophan pellagra

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. 

Pellagra Can Occur as a Result of Disease Despite an Adequate Intake of Tryptophan Niacin... 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

A deficiency of niacin in the diet results in the disease known as pellagra, characterized by the four D s diarrhea, dermatitis, dementia, and death. In the early years of the twentieth century in the United States, pellagra was common among poor tenant farmers and mill workers in the rural South. The diet there at that time was rich in com that contained little niacin and little available tryptophan from which to synthesize it. 

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. 

The classical niacin deficiency disease is pellagra, which is characterized by symptoms including diarrhoea, dermatitis, dementia and eventually death. High-protein diets are rarely deficient in niacin since, in addition to the preformed vitamin, such diets supply sufficient tryptophan to meet dietary requirements. Large doses of niacin can cause the dilation of capillaries, resulting in a painful tingling sensation. 

FIGURE 13-17 Structures of niacin (nicotinic acid) and its derivative nicotinamide. The biosynthetic precursor of these compounds is tryptophan. In the laboratory, nicotinic acid was first produced by oxidation of the natural product nicotine—thus the name. Both nicotinic acid and nicotinamide cure pellagra, but nicotine (from cigarettes or elsewhere) has no curative activity. 

The daily requirement for an adult is about 7.5 mg. The amount is decreased by the presence in the diet of tryptophan, which can be converted partially to nicotinic acid (Chapter 25).d e Tryptophan is about 1 /60 as active as nicotinic acid itself. The one-time prevalence of pellagra in the southern United States was a direct consequence of a diet high in maize whose proteins have an unusually low tryptophan content. 

Tryptophan provides some of the human daily niacin requirements. Hence niacin deficiency with pellagra-like symptoms develops if the diet contains insufficient amounts of tryptophan. 

The disturbance of tryptophan metabolism in riboflavin deficiency, caused by impairment of kynurenine hydroxylase, can also result in reduced synthesis of NAD from tryptophan. This may therefore be a factor in the etiology of pellagra (Section 8.3.3.1). 

After it had been established that pellagra was a nutritional deficiency disease, the next problem was to discover the missing nutrient. Additional dietary protein was shown to be beneficial, thus it was concluded that pellagra was because of a protein deficiency. This view, and later that it was more specifically from a deficiency of tryptophan, was held for some time. In 1938, Spies and coworkers showed that nicotinic acid would cure pellagra thereafter it was gradually accepted that it was a niacin deficiency disease. 

During the first half of the twentieth century, when 87,000 people died from pellagra in the United States, there was a two-fold excess of females over males. Reports of individual outbreaks of pellagra show a similar sex ratio. This may well be the result of inhibition of kynureninase, and impairment of the activity of kynurenine hydroxylase, by estrogen metabolites, and hence reduced synthesis of NAD from tryptophan (Bender and Totoe, 1984b). 

Kynurenine Hydroxylase Kynurenine hydroxylase is an FAD-dependent mixed-function oxidase of the outer mitochondrial membrane, which uses NADPH as the reductant. The activity of kynurenine hydroxylase in the liver of riboflavin-deficient rats is only 30% to 50% of that in control animals, and deficient rats excrete abnormally large amounts of kynurenic and anthranilic acids after the administration of a loading dose of tryptophan, and, correspondingly lower amounts of quinolinate and niacin metabolites. Riboflavin deficiency may thus be a contributory factor in the etiology of pellagra when intakes of tryptophan and niacin are marginal (Section 8.5.1). 

The other characteristic feature of pellagra is the development of a depressive psychosis, superficially similar to schizophrenia and the organic psychoses, but clinically distinguishable by the sudden lucid phases that alternate with the most florid psychiatric signs. The mental symptoms may be the result of tryptophan depletion, and hence a lower availability of tryptophan for synthesis of the neurotransmitter serotonin (5-hydroxytryptophan). But the role of cADP-ribose and NAADP in controlling calcium release in response to neurotransmitters (Section 8.4.4) and impaired energy-yielding metabolism in the central nervous system as a result of depletion of NAD (P) may also be important. 

It is likely that leucine is only a factor in the etiology of pellagra when the dietary intakes of both tryptophan and niacin are extremely low - a condition that may occur when sorghum is the dietary staple, especially during food shortage. 

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 is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

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