Nicotinamide deamidase

Figure 8.2. Synthesis of NAD from nicotinamide, nicotinic acid, and qninolinic acid. Quinolinate phosphoribosyltransferase, EC 2.4.2.19 nicotinic acid phosphoribosyl-transferase, EC 2.4.2.11 nicotinamide phosphoribosyltransferase, EC 2.4.2.12 nicotinamide deamidase, EC 3.5.1.19 NAD glycohydrolase, EC 3.2.2.S NAD pyrophosphatase, EC 3.6.1.22 ADP-ribosyltransferases, EC 2.4.2.31 and EC 2.4.2.36 and poly(ADP-ribose) polymerase, EC 2.4.2.30. PRPP, phosphoribosyl pyrophosphate.

Figure 8.3. Metabolites of nicotinamide and nicotinic acid. Nicotinamide deamidase (nicotinamidase), EC 3.5.1.19 nicotinamide Af-methyltransferase, EC 2.1.1.1 aldehyde dehydrogenase, EC 1.1.1.1. Relative molecular masses (Mr) nicotinamide, 123.1 nicotinic acid, 122.1 nicotinamide JV-oxide, 139.1 Af -methyl nicotinamide, 139.1 trigonelline, 137.1 nicotinuric acid, 179.2 and methyl pyridone carboxamides, 154.1.

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). 

Why might it be desirable to coordinately lower the levels of nicotinamide deamidase The 8-fold depression in nicotinamide deamidase activity causes excretion of nicotinamide xthR mutants have shown to be "feeders" for nicotinamide auxotrophs, indicating that these strains continuously excrete nicotinamide into the medium. This is presumably a consequence of the pyridine nucleotide cycle, shown in Fig. 2. Nicotinamide deamidase is not only an enzyme for the salvage of exogenous pyridine, but it is part of a NAD recycling pathway, i.e., a "pyridine nucleotide cycle"... 

Any intracellular nicotinamide which is produced from NAD, either directly or indirectly (from NMN), must be deamidated to nicotinic acid before it can be resynthesized into NAD. When nicotinamide deamidase levels faU, intracellular nicotinamide is not efficiently recycled, and a significant fraction of nicotinamide produced by pyridine nucleotide cycles is excreted into the medium. Thus, lowering nicotinamide deamidase levels shunts the normal pyridine nucleotide cycle to cause excretion of nicotinamide. 

Fig. 2. Intracellular pyridine nucleotide cycles in enteric bacteria. The breakdown and resynthesis of NAD occurs in bacteria by the metabolic steps shown above. All abbreviations are as in Fig. 1, with the addition of NMN, nicotinamide mononucleotide. The metabolic step catalyzed by nicotinamide deamidase, the levels of which are reduced by anxt/iR mutation (see text) is shown by the bold arrow.

Deamidation of Nicotinic Add. Enzymes from microorganisms (185-188), insects (189), and birds have been found to deamidate nicotinamide to nicotinic acid (190). Recently, Sundaram et al. (191) have shown that a strain of Leuconostoc mesenteroides which will grow on nicotinic acid but not on nicotinamide, does not possess the deamidase and will not convert the pyridine amide to DPN. On the other hand, Saccharomyces cerevisiae will grow on both pyridine compounds, and the yeast contains the deamidase. These observations suggest that the route of synthesis of DPN from nicotinamide may involve the Preiss-Handler pathway, and that deamidation of nicotinamide occurs during the synthesis, which is also indicated by studies in the intact mouse (see Section III, A). 

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