NAD synthesis

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. 

M. Hasmarm, L. B. Saltz and J. A. Koutcher, Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by H-decoupled- P magnetic resonance spectroscopy. Clin. Cancer Res., 2005,11,3503-3513. 

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). 

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metaboUte quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normal conditions, almost aU of the dietary intake of tryptophan, apart from the small amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is by way of 5-hydroxylation and decarboxylation to 5-hydroxytryptarnine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

It is thus apparent that the utilization of tryptophan as a precursor for NAD synthesis depends on both the amount of tryptophan to be metabolized and also the rate of metabolic flux through the pathway. The activities of three... 

In isolated hepatocytes, after maximum induction of tryptophan dioxygenase by glucocorticoids, the uptake of tryptophan into the cells has a control coefficient of 0.75, whereas the control coefficient of tryptophan dioxygenase falls to 0.25. Therefore, the induction of tryptophan dioxygenase has only a limited effect on tryptophan catabolism and NAD synthesis (Salter and Pogson, 1985 Salter et al., 1986). In isolated perfused liver, although cortisol leads to a several-fold increase in tryptophan dioxygenase activity, there is only a relatively small increase in the rate of clearance of tryptophan from the perfusion medium (Kim and Miller, 1969). 

Magni G, Amici A, Emanuelli M, Raffaelli N, and Ruggieri S (1999) Enzymology of NAD+ synthesis. Advances in Enzymology and Related Areas of Molecular Biology 73, 135-82, xi. 

Inhibitors based on the structure of nicotinamide or benzamide have been reported to have toxicity problems arising from the fact that some of them may be antimetabolites for NAD synthesis or interact with other NAD... 

Not only are the effects of thiadiazoles blocked in patients, but the antileukemic action in experimental animals is also reversed by nicotinamide (C3). No direct evidence of interference with NAD synthesis or function has been obtained, but these reversal studies obviously suggest this as a possible explanation of the biochemical actions of these compounds. Ciotti and associates (C3) demonstrated an exchange reaction with NAD in vitro yielding an analog of NAD, but no evidence was obtained that this occurs in vivo. 

Activity of NAPRT was increased in P. falciparum-infected red blood cells as was nicotinamide synthase and nicotinamide deamidase NAAD and NAD phosphorylase remained at similar levels upon infection. It was concluded that the majority of NAD synthesis in P. falciparum occurs from both nicotinic acid and nicotinamide via nicotinamide deamidase, NAPRT, NAAD phosphorylase and NAD synthase (Zerez et ah, 1990). None of the genes for these enzymes has been cloned neither have the enzymes been isolated. However, evidence for them can be found in the P. falciparum genome database (http //www.plasmodb.org last accessed 16 July 2008). 

Abbreviations (symbols) used for enzymes and respective enzymatic reactions are the same as in Figure 2 and in the individual reaction diagrams (Schemes 1-7). Note that the same symbols may be used for distinct enzyme families as long as they catalyze the same reaction in NAD synthesis. 

NMPRT enzyme that converts Nm directly into NMN was originally characterized as a product of the nadV gene in Haemophilus ducreyi This organism, as most other members of Pasteurellaceae, lacks the machinery for amidation of the pyridine carboxylate (as well as most other enzymes of NAD synthesis, see Section... 

Overall, one may observe that the NadM family reveals a high degree of functional versatility affording variations in both substrate specificity and physiological role. These variations are prominent within the bacterial kingdom where the members of the NadM family are sparsely distributed. This is in contrast with archaea where NadM appears to be a completely universal housekeeping enzyme in the main route of NAD synthesis (an archaeal equivalent of NadD). 

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