Nicotinic acid mononucleotide

The result of this biosynthesis is that the product is nicotinic acid mononucleotide rather than free nicotinic acid. Ingested nicotinic acid is converted to nicotinic acid mononucleotide which, in turn, is converted to nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide. If excess nicotinic acid is ingested, it is metabolized into a series of detoxification products (Fig. 4). Physiological metabohtes include /V-methylnicotinamide (19) and A/-methyl-6-pyridone-2-carboxamide (24) (1). 

The niacin vitamers in foods include nicotinic acid and nicotinamide (Fig. 4), which occur in limited quantities in the free form, and their coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) (93,96). The nicotinic acid analog of NAD as well as nicotinamide and nicotinic acid mononucleotides also occur in nature. In addition, niacin occurs as nicotinyl esters bound to polysaccharides, peptides, and glycopep-tides, which are known as niacytin and niacynogens, respectively. In general, the niacin vitamers in cereal grains and other seeds are principally the nicotinic acid forms, whereas those in meat and fish are primarily the nicotinamide forms (94,95). 

Figure 6. Proposed pyridine nucleotide cycle. Abbreviations NaMN, nicotinic acid mononucleotide NaAD, nicotinic acid adenine dinucleotide and NAD, oxidized form of nicotinamide adenine dinucleotide.

B) in plants and bacteria. 50, dihydroxyacetone phosphate 51 tryptophan 52, hydroxyanthranilic acid 53, quinolinic acid 54, aspartate 55, nicotinic acid mononucleotide 56, NAD, 57, NADP. 

Nicotinic acid and nicotinamide and their derivatives were analyzed by TLC on MN 300G cellulose plates in various solvent systems (K. Shibata, personal communications, October 16, 2001). The Rf values of nicotinamide adenine dinucleotide phosphate or NADP" (Rf values 0.03, 0.50, and 0.70), nicotinamide adenine dinucleotide or NAD" (Rf values 0.13, 0.61, and 0.58), nicotinic acid adenine dinucleotide (Rf values 0.15, 0.52, and 0.57), nicotinamide mononucleotide (Rf values 0.11, 0.63, and 0.73), nicotinic acid mononucleotide (Rf values 0.13, 0.47, and 0.75), nicotinamide (Rf values 0.87, 0.88, and 0.45), and nicotinic acid (Rf values 0.77, 0.82, and 0.55) are shown in various solvent systems [1 M ammonium acetate-95 % ethanol (3 7), pH 5.0 2-butyric acid-ammonia-water (66 1.7 33), and 600 g of ammonium sulfate in 0.1 M sodium phosphate-2% 1-propanol (pH 6.8), respectively]. The detection is performed by illumination under short-wavelength (257.3 nm) UV light. Urinary metabolites of the vitamin could be analyzed by TLC. ... 

In the human, nicotinic acid reacts with 5-phosphoribosyl-I-pyrophosphate to form nicotinic acid mononucleotide, which then reacts with ATP to produce desamido-NADIthc intermediate dinucleotide with the nicotinic acid moiety). Finally, the latter intermediate is converted to NAD (originally called coenzyme I) by transformation of the emboxyl of the nicotinic acid moiety to the amide by glutamine. Thb final step is catalyzed by NAD synthetase NADP is produced from NAD by ATT under kinase catalysis. ... 

Pellagra is currently thought to be due to imbalance of dietary amino acids and deficiency of niacin. The common variety of maize is rich in leucine, which inhibits synthesis of nicotinic acid mononucleotide and causes deficiency of NAD+ and NADP+. A strain of maize known as opaque 2 contains less leucine and does not cause pellagra unless excess leucine is added to the diet. 

Figure 2 NAD biosynthesis subsystem diagram. Major functional roles are shown by 4-6 letter abbreviations (explained in Table 1) over the colored background reflecting the key aspects or modules (pathways) that comprise NAD biosynthesis in various species. Catalyzed reactions are shown by solid straight arrows, and corresponding intermediate metabolites are shown as abbreviations within ovals Asp, L-aspartate lA, Iminoaspartate Qa, quinolinic acid Nm, nicotinamide Na, nicotinic acid NaMN, nicotinic acid mononucleotide NMN, nicotinamide mononucleotide RNm, N-ribosyInicotinamide NaAD, nicotinate adenine dinucleotide NAD, nicotinamide adenine dinucleotide NADP, NAD-phosphate Trp, tryptophan FKyn, N-formylkynurenine Kyn, kynurenine HKyn, 3-hydroxykynurenine HAnt, 3-hydroxyanthranilate and ACMS, a-amino-/3-carboxymuconic semialdehyde. Unspecified reactions (including spontaneous transformation and transport) are shown by dashed arrows.

As an alternative to nicotinamide, quinolinic acid (a degradation product of tryptophan) may be used to form nicotinic acid mononucleotide (NaMN). Quinolinic acid contains two carboxyl groups one of which is cleaved off during the reaction. All known NMNATs may use NaMN to form a dinucleotide and the subsequent reaction with ATP then yields nicotinic acid adenine dinucleotide, NAAD. This intermediate is the substrate of NAD synthase, an enzyme... 

Quinolinic acid phosphoribosyl transferase (PT) catalyzes the formation of nicotinic acid mononucleotide (NaMN) from quinolinic acid and phosphoribosyl pyrophosphate. The pyridine nucleotide NaMN reacts with ATP (adenosine Hiphos-phate) upon mediation of NaMN adenylyltransferase to form the nicotinic acid adenine dinucleotide (NaAD) (Figure 6.7). The latter is converted to NAD by NAD synthetase. NADP is formed from NAD by the catalysis of NAD kinase. 

The conversion of nicotinic acid mononucleotide to NAD proceeds in two metabolic steps, with nicotinic acid dinucleotide (NaAD) as an intermediate (4) there are no alternative metabolic steps for the synthesis of NAD from NaMN. Thus, the genes that control these two metabolic steps should be essential for viability, and conditional-lethal mutations should be recovered. 

Q -D-(5 )i.-/o/ m P-Me, M-178 Methyl 2,3-di-0-methyl-4-thioglucopyranoside 4,6-cyclic phosphonothioate a-D-(5 )p-/orm P-Chloro, M-I79 Methyl 2,3-di-0-methyl-4-thioglucopyranoside 4,6-cyclic phosphonothioate a-D-(P)p-/orm P-Ethoxy, M-179 Methyl 2,3-di-0-methyl-4-thioglucopyranoside 4,6-cyclic phosphonothioate a-D-(5 )p-/o/7n P-Ethoxy, M-179 2-Methyladenosine 5 -Phosphate, M-223 7-Methylguanosine 5 -Phosphate, M-262 Monobutyl 3"-adenylate, A-31 Nicotinamide ribonucleotide, N-45 Nicotinic acid mononucleotide, N-46... 

In most bacteria and in higher plants nicotinic acid is formed from aspartic acid and a three carbon unit derived from glycerol, probably D-glyceraldehyde-3-phosphate (D 2). A key intermediate is quinolinic acid, which in animals, however, is derived from l-tryptophan (D 21). Nicotinic acid originates from quinolinic acid via nicotinic acid mononucleotide formed with the participation of 5-phosphoribosyl-l-pyrophosphate. It changes either directly to nicotinic acid or is formed via nicotinamide adenine dinucleotide (NAD+) in the nicotinic acid nucleotide cycle. 

Thus, in the cell, the newly synthesized NAD is faced with several foes, and the cell must either provide NAD at a rate more rapid than that at which the coenzyme is hydrolyzed, or the new NAD must be kept separate from the catabolic enzymes. The intracellular distribution of the enzymes involved in NAD metabolism, therefore, is of capital interest. The enzyme that catalyzes the formation of deamido NAD from ATP and nicotinic acid mononucleotide is in the nucleus, as was first shown by Hogeboom and Schneider [93]. Later, Elyane Baltus also demonstrated that, at least in the starfish, this reaction is restricted to the nucleolus [94]. 

The third hypothesis has found some support from the work of Pardee [96] and his collaborators. These investigators studied in Escherichia coli the activity of nicotinic acid, mononucleotide pyrophosphorylase, nicotinic acid dinucleotide pyrophosphorylase, NAD... 

Nicotinic acid mononucleotide reacts with ATP in the presence of nicotinic acid adenine dinucleotide pyrophosphorylase, a magnesium-dependent enzyme, to yield the deamido derivative of NAD (see Fig. 4-11). Deamido NAD, in the presence of ATP, glutamine, Mg, K", and an NAD synthetase, is converted to NAD. In this reaction, the amino group of glutamine is transferred to the carboxyl group of the nicotinic acid moiety of deamido NAD. Yet the nicotinamide moiety of NAD synthetase is found in liver supernatant and, as may be expected, it is inhibited by azaserine. 

Quinolinate decarboxylation and conversion to nicotinic acid mononucleotide is catalysed by quinolinate phosphoribosyltransferase, a rate-limiting enzyme in the conversion of tryptophan to NAD the reaction requires Mg and is negatively regulated by nicotinamide. Next the transfer of adenylate from ATP by an intermediate of nicotinamide/nicotinate-mononucleotide-adenyl-transferases isoenzymes (NMNAT, see below) yields nicotinic acid adenine... 

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