Niacin from tryptophan

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. 

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. 

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. 

The definition of a vitamin has been extended by some (Spector, 1980) to Include those chemical compounds required by a specific tissue but not synthesized by that tissue. For example. In certain species, vitamin C can be synthesized from glucose In the liver but not In the Central Nervous System therefore, vitamin C Is not considered a vitamin for these animals. Vitamin C for the brain must be drawn from the blood, from the vitamin C that entered the blood from the diet, or was synthesized In the liver. Subsequently, vitamin C could be considered a vitamin for the brain since It must be obtained from outside the brain. Another example Is the vitamin niacin, which cannot be synthesized from tryptophane In mammalian brain however, the synthesis of niacin from tryptophane occurs In mammalian liver (Spector and Kelly, 197.9 Spector, 1979). 

Only a few ducklings are able to survive at the low level of 50 mg/100 gm diet of tryptophan, whereas all survive at a supplement of 1 gm/100 gm diet. Although the results are still preliminary, they suggest that there may be a genetic factor in the ability of animals to utilize tryptophan as a growth factor in the absence of niacin. It is possible that the difference in response of the individual birds may be due to a quantitative or qualitative difference in the enzymes involved in the formation of niacin from tryptophan. The individuals, growing in the absence of either added nicotinamide or tryptophan, may have an enzyme complement particularly efficient in promoting the synthesis of the vitamin from tryptophan. 

Pyridoxine is involved as a co-factor coenzyme in about 100 enzyme systems. Thus, in addition to the reactions mentioned above, it is required for glycogen phosphoryl-ase, which catalyses the release of glucose from stored glycogen, haemoglobin biosynthesis, the generation of glucose from amino acids (gluconeogenesis), the biosynthesis of niacin from tryptophan and nucleic add biosynthesis. 

In this regard, tryptophan is considered a provitamin and is assigned a niacin equivalent of 1/60. The following fists the vitamin content of many common foodstuffs and in Table 3, values of vitamin B content are compared to niacin potential from tryptophan. 

NAD(H) from niacin (some may be synthesized from tryptophan)... 

Riboflavin (vitamin Bj) is chemically specified as a 7,8-dimethyl-10-(T-D-ribityl) isoalloxazine (Eignre 19.22). It is a precnrsor of certain essential coenzymes, such as flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) in these forms vitamin Bj is involved in redox reactions, such as hydroxylations, oxidative carboxylations, dioxygenations, and the reduction of oxygen to hydrogen peroxide. It is also involved in the biosynthesis of niacin-containing coenzymes from tryptophan. 

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. 

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. 

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. 

Distribution and Sources. In plants, niacin production sites occur in leaves, germinating seeds, and shoots. In humans, niacin is not available from intestinal bacteria, but some conversion is made from tryptophan which occurs in tissues. 

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. 

In the liver, there is litde utilization of preformed niacin for nucleotide synthesis. Although isolated hepatocytes will take up both vitamers from the incubation medium, they seem not to be used for NAD synthesis and cannot prevent the fall in intracellular NAD(P), which occurs during incubation. The enzymes for nicotinic acid and nicotinamide utilization are more or less saturated with their substrates at normal concentrations in the liver, and hence are unlikely to be able to use additional niacin for nucleotide synthesis. By contrast, incubation of isolated hepatocytes with tryptophan results in a considerable increase in the rate of synthesis of NAD(P) and accumulation of nicotinamide and nicotinic acid in the incubation medium. Similarly, feeding experimental animals on diets providing high intakes of nicotinic acid or nicotinamide has relatively little effect on the concentration of NAD (P) in the liver, whereas high intakes of tryptophan lead to a considerable increase. It thus seems likely that the major role of the liver is to synthesize NAD(P) from tryptophan, followed by hydrolysis to release niacin for use by extrahepatic tissues (Bender et al., 1982 McCreanor and Bender, 1986 Bender and Olufunwa, 1988). 

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. 

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

Animals and yeasts can synthesize nicotinamide from tryptophan via hydroxyanthranilic acid (52) and quinolinic acid (53, Fig. 6A) (31), but the biosynthetic capacity of humans is limited. On a diet that is low in tryptophan, the combined contributions of endogenous synthesis and nutritional supply of precursors, such as nicotinic acid, nicotinamide, and nicotinamide riboside, may be insufficient, which results in cutaneous manifestation of niacin deficiency under the clinical picture of pellagra. Exogenous supply of nicotinamide riboside was shown to promote NAD+-dependent Sir2-function and to extend life-span in yeast without calorie restriction (32). 

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. 

Nicotinate (also called niacin or vitamin Bg) is derived from tryptophan. Human beings can synthesize the required amount of nicotinate if the supply of tryptophan in the diet is adequate. However, nicotinate must be obtained directly if the dietary intake of tryptophan is low. A dietary deficiency of tryptophan and nicotinate can lead to pellagra, a disease characterized by dermatitis, diarrhea, and dementia. An endocrine tumor that consumes large amounts of tryptophan in synthesizing the hormone and neurotransmitter serotonin (5-hydroxytryptamine) can lead to pellagralike symptoms. 

Vitamin B5 Niacin (= nicotinic acid) and niacinamide (= nicotinamide) are supplied in the diet and converted in the body into the coenzymes nicotinamide-adenine dinucleotide (NAD) and nicotinamide-adenine dinucleotide phosphate (NADP). These coenzymes are important in tissue respiration. Nicotinic acid can also be formed from tryptophan via kynolin acid. 

Serotonin and melatonin are derived from tryptophan, as is the nicotinamide portion of NAD+ (which is also derived from the vitamin niacin). 

Pellegra is caused by a deficiency of the vitamin niacin or of tryptophan. Niacin is required for the production of NAD and NADP. These compounds may also be generated from tryptophan. Pellegra results in the four D s dermatitis, diarrhea, dementia, and death. 

E. Although niacin is a vitamin, it may be synthesized to a limited extent from tryptophan. The other compounds are required in the diet. 

A 70-B. Although dietary niacin is the major source of the nicotinamide ring of NAD, it may also be produced from tryptophan. 

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