The Synthesis of Nicotinamide Nucleotides from Tryptophan

A number of studies have investigated the equivtdence of diettuy tryptophan and preformed niacin as precursors of the nicotintimide nucleotides, generally by determining the excretion of -methyl nicotinttmide emd methyl pyridone carboxamide in response to test doses of the precursors, in subjects maintained on deficient diets. 

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 tryptophem 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 tryptophem. 

Changes in hormonal status may result in considerable changes in this ratio, between 7 to 30 mg of dieteuy tryptophem equivalent to 1 mg of preformed niacin in late pregnancy. The inteike of tryptophan also affects the ratio. At low inteikes, 1 mg of tryptophan may be equiveilent to only 1/125 mg of preformed niacin (Neikagawa et al., 1969). 

Tryptophan dioxygenase (Section 8.3.2) is only found in the liver other tissues have em indoleamine dioxygenase, with lower specificity, that cateilyzes the same reaction. However, the pathway for onwend metabolism of kynure-nine is found only in liver and mononucleeu phagocytes, and induction of in-doleeimine dioxygenase by cytokines, such as interferon-y, leads to increased circulating concentrations and urineuy excretion of kynurenine, with little or 

1 Picoiinate Carboxylase and Nonenzymic Cyclization to Quinolinic Acid 

As might be expected, the synthesis of NAD from tryptophem is inversely related to the activity of picoiinate carboxylase. Inhibition with pyiazineunide results in increased avtulability of aminocarhoxymuconic semieddehyde, and hence increased NAD formation. Equally, activation of picoiinate carboxylase results in reduced availability of euninoccu boxymuconic semieddehyde for cyclization, emd hence a reduced formation of NAD. 

---

It is not strictly correct to regard niacin as a vitamin. Its metabolic role is as the precursor of the nicotinamide moiety of the nicotinamide nucleotide coenzymes, nicotinamide adenine dinucleotide (NAD) and NADP, and this can also be synthesized in vivo from the essential amino acid tryptophan. At least in developed countries, average intakes of protein provide more than enough tryptophan to meet requirements for NAD synthesis without any need for preformed niacin. It is only when tryptophan metabolism is disturbed, or intake of the amino acid is inadequate, that niacin becomes a dietary essential. 

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). 

Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

The alkaloids interfere with a number of enzyme systems. In vitro, lasiocarpine and heliotrine inhibit enzyme systems that need pju idine nucleotides for electron transfer (45). The nicotinamide-adenine dinucleotide pyrophosphorylase activity of nuclei from rat liver that has been treated with heliotrine is reduced significantly below that of controls (46). It has recently been shown that in rats lasiocarpine inhibits RNA synthesis, causes a substantial reduction in tryptophan pyrrolase activity, and decreases the activity of RNA polymerase (47). 

Analysis of nicotinic acid, nicotinamide, and its metabolites in biological materials, i.e., blood, plasma, urine, and tissues, is important in studies on biochemical pathways (Hengen and deVries, 1985). Finder et al. (1971) described several paper and thin-layer chromatographic systems useful for the differentiation of nucleotides in tissues derived from nicotinamide and nicotinic acid. Hengen and deVries (1985) provided a table summarizing the Rp values of nicotinic acid, nicotinamide, and various intermediates of NAD+ and NADP-I- synthesis for both paper and thin-layer chromatography. Haworth and Walmsley (1972) used two-dimensional TLC on silica gel for the identification of tryptophan metabolites in urine and resolved 32 compounds including nicotinic acid and nicotinamide. Kala et al. (1978) used silica gel TLC to examine urine for nicotinic acid and its metabolites after administration of nicotinyl alcohol. They... 

As shown in Figure 11.13, the nicotinamide nucleotide coenzymes can be synthesized from either of the niacin vitamers, and from quinolinic acid, an intermediate in the metabolism of tryptophan. In the liver, the oxidation of tryptophan results in a considerably greater synthesis of NAD than is required, and this is catabolized to release nicotinic acid and nicotinamide, which are taken up and used by other tissues for synthesis of the coenzymes. 

---