Tryptophan niacin and

Bender DA and Bender AE (1986) Niacin and tryptophan metaboiism the hiochemicai basis of niacin requirements and recommendations. Nutrition Abstracts and Reviews (Series A) 56, 695-719. 

DEFICIENCY Pellagra. Niacin may be produced from tryptophan (1-8). Niacin deficiency therefore is most likely in persons with low intake of both niacin and tryptophan. People who eat mainly com may develop niacin deficiency as com is low in tryptophan. In pellagra, the patient develops the 3 D s Diarrhea, Dermatitis, and Dementia. Diagnostic testing is difficult and may best be done by seeing improvement with niacin ingestion. 

Deficiencies were common in populations vdiose main calorie source was com (51, 52). Zein is the main protein found in com and it is very low in both niacin and tryptophan. When com is ground with lime water, the small amounts of niacin and tryptophan become more bioavailable. Populations who consume com... 

Pellagra was originally thought to be due to inadequate dietary niacin and tryptophan. In some parts of the world, it is associated with consumption of diets high in maize (American corn), which, like other cereal grains, is relatively deficient in tryptophan and niacin. In addition, about 20% of the niacin in maize is protein-bound and not biologically available. Several bound forms of niacin have been characterized. They include niacinogens (peptides of M.W. 12,000-13,000) and niacytin, isolated from wheat (M.W. 2370). 

Riboflavin has a wide distribution in foods, and small amounts are present as coenzymes in most plant and animal tissues. Eggs, lean meats, milk, broccoli, and enriched breads and cereals are especially good sources. A portion of our niacin requirement can be met by synthesis from tryptophan. Meat (especially red meat), liver, legumes, milk, eggs, alfalfa, cereal grains, yeast, and fish are good sources of niacin and tryptophan. 

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. 

Our species has lost the ability to make vitamins. Thus, deficiency of niacin (nicotinamide), the N in NAD, leads to the disease pellagra, a collection of skin, intestinal, and neurological symptoms. (Niacin can be synthesized from the amino acid tryptophan, so pellagra results from a deficiency of both niacin and tryptophan in the diet.)... 

Deficiency diseases pellagra (from the Italian rough skin ) occurs if diet Is deficient in BOTH niacin and tryptophan such as maize-based diets (dermatitis, diarrhoea, dementia)... 

The reasons for niacin deficiency in individuals nourished on a corn or maize diet are still not clear. Corn is low in niacin and tryptophan, but it is also possible that the niacin in corn forms a chemical complex that cannot be used therefore, the lime treatment of the corn used in Central American diets may be important in preventing pellagra. Niacin is not the active molecule in the body. The importance of niacin, as we have previously seen, stems from its role in NAD and NADP synthesis, and the deficiency can be expected to lead to reduced NAD and NADP concentrations in liver and blood serum. However, the exact significance of this reduction is not clear. Up to now, it has been impossible to establish a direct correlation between the growth rate and the amount of NAD in the liver. 

RECOMMENDED DAILY ALLOWANCE OF NIACIN. Estimation of niacin requirements are complicated (1) by the fact that some tryptophan is converted to niacin in man, (2) by the paucity of people of different ages receiving diets varying in niacin and tryptophan content, and (3) by the possible unavailability of niacin in some foods (such as corn). 

Coffee is a good source of niacin (a dark roast provides about 3 mg of niacin per cup). In certain areas of the world where the diet of the people is low in niacin and tryptophan, their high consumption of coffee may explain their low incidence of pellagra. 

Deficiency in animals affects the skin and digestive tract. Ruminants on green fodder usually do not require extra niacin, but niacin supplements improve milk yield in cows. Pellagra is a disease resulting from a combined deficiency of niacin and tryptophan. The symptoms of pellagra include dermatosis, dementia, diarrhoea and nervous disorders. Pellagra is rarely seen in industrialized countries and is associated with alcohol abuse. In other parts of the world where maize is the major staple diet, pellagra persists. 

Other Additives. Cats cannot convert tryptophan to niacin (22), or carotene to vitamin A in sufficient amounts to meet thein needs (23). These deviations, as compared with other animals, need not produce problems because added dietary sources of niacin and vitamin A provide the needs of cats. 

The RDA for niacin is based on the concept that niacin coen2ymes participate in respiratory en2yme function and 6.6 niacin equivalents (NE) are needed per intake of 239 kj (1000 kcal). One NE is equivalent to 1 mg of niacin. Signs of niacin deficiency have been observed when less than 4.9 NE/239 kj or less than 8.8 NE per day were consumed. Dietary tryptophan is a rich source of niacin and the average diet in the United States contains 500—1000 mg of tryptophan. In addition, the average diet contains approximately 8—17 mg of niacin. In total, these two quantities total 16—34 NE daily. Table 5 Hsts the RDA and U.S. RDA for niacin (69). 

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. 

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. 

Milk contains about 0.1 mg niacin per 100 g and thus is not a rich source of the preformed vitamin. Tryptophan contributes roughly 0.7 mg NE per 100 g milk. In milk, niacin exists primarily as nicotinamide and its concentration does not appear to be affected greatly by breed of cow, feed, season or stage of lactation. Pasteurized goats (0.3 mg niacin and 0.7 mg NE from tryptophan per 100 g) and raw sheep s (0.4 mg niacin and 1.3 mg NE from tryptophan per 100 g) milk are somewhat richer than cows milk. Niacin levels in human milk are 0.2 mg niacin and 0.5 mg NE from tryptophan per 100 g. The concentration of niacin in most dairy products is low (Appendix 6A) but is compensated somewhat by tryptophan released on hydrolysis of the proteins. 

Vitamin B6 occurs naturally in three related forms pyridoxine (6.26 the alcohol form), pyridoxal (6.27 aldehyde) and pyridoxamine (6.28 amine). All are structurally related to pyridine. The active co-enzyme form of this vitamin is pyridoxal phosphate (PLP 6.29), which is a co-factor for transaminases which catalyse the transfer of amino groups (6.29). PLP is also important for amino acid decarboxylases and functions in the metabolism of glycogen and the synthesis of sphingolipids in the nervous system. In addition, PLP is involved in the formation of niacin from tryptophan (section 6.3.3) and in the initial synthesis of haem. 

This value includes niacin equivalents from preformed niacin and from tryptophan. A dietary intake of 60 mg tryptophan is considered equivalent to 1 mg niacin. One niacin equivalent is equal to either to those amounts. 

Niacin and riboflavin are converted to their respective coenzymes, NAD+ and NADP+ on the one hand and flavin munonucleotide (FMN) and flavin adenine dinucleotide (FAD) on the other, as described in Chapter 10. Some NAD+ can be synthesized from tryptophan, as described in Chapter 20. Tryptophan, however, provides only a fraction of our daily NAD+ requirements. 

The most extensive such study was that of Horwitt and coworkers (1956). They found that there was a considerable variation between subjects in the response to tryptophan and niacin, and suggested that in order to allow for individual variation, it should be assumed that 60 mg of tryptophan was equivalent to 1 mg of preformed niacin. This ratio has been generally accepted, and is the basis for expressing niacin requirements and intake in terms of niacin equivalents - the sum of preformed niacin and 1 /60 of the tryptophan. 

The result of this is that at low rates of flux through the kynurenine pathway, which result in concentrations of aminocarhoxymuconic semialdehyde below that at which picolinate carboxylase is saturated, most of the flux will be byway of the enzyme-catalyzed pathway, leading to oxidation. There will be Utde accumulation of aminocarhoxymuconic semialdehyde to undergo nonenzymic cyclization. As the rate of formation of aminocarhoxymuconic semialdehyde increases, and picolinate carboxylase nears saturation, there will be an increasing amount available to undergo the nonenzymic reaction and onward metabolism to NAD. Thus, there is 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. 

Cats, which have some 30- to 50-fold higher activity of picolinate carboxylase than other species, are entirely reliant on a dietary source of preformed niacin, and are not capable of any significant synthesis of NAD from tryptophan. 

Despite our understanding of the biochemistry of niacin, we still cannot account for the characteristic photosensitive dermatitis in terms of the known metabolic lesions. There is no apparent relationship between reduced availability of tryptophan and niacin, and sensitivity of the skin to ultraviolet (UV) light. The only biochemical abnormalities that have been reported in the skin of pellagrins involve increased catabolism of the amino acid histidine leading to a reduction in the concentration of urocanic acid, a histidine metabolite that is the major UV-absorbing compound in normal dermis (see Figure 10.6). 

Niacin and niacinamide refer to nicotinic acid and its amide. Nicotinic acid is a pyridine derivative synthesized from tryptophan. 

Hartnup s disease. There is a defect in the epithelial transport of neutral amino acids (e.g., tryptophan) leading to poor absorption and excess excretion of these amino acids. Clinical signs resemble those of niacin deficiency (tryptophan is a precursor of niacin), namely the 3 D s Diarrhea, Dementia, Dermatitis. The condition responds to nicotinamide administration. Fan-coni s syndrome is a more generalized defect in molecular transport, involving a multitude of amino acids, glucose, calcium, phosphate, proteins, and other molecules. There may be decreased growth and rickets. 

Niacin is not a true vitamin in the strictest definition since it can be derived from the amino acid tryptophan. However, the ability to utilize tryptophan for niacin synthesis is inefficient (60 mg of tryptophan are required to synthesize 1 mg of niacin). Also, synthesis of niacin from tryptophan requires vitamins Bi, B2 and Bg, which would be limiting in them on a marginal diet. 

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoaceticacid, Iryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-Co A, formic add, four molecules of carbon dioxide, and two ammonium ions One of the intermediates of tryptophan catabolism, a-amino-P-carboxyrnuconic-6-semialdchydc, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

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