NAD+ synthetase

NAD+ synthetase (ammonia-utilizing) [EC 6.3.1.5] catalyzes the reaction of ATP with deamido-NAD+ and ammonia to produce NAD+, AMP, and pyrophosphate (or, diphosphate). NAD+ synthetase (glutamine-utilizing) [EC 6.3.5.1] catalyzes the reaction of ATP with deamido-NAD+, glutamine, and water to produce NAD+, glutamate, AMP, and pyrophosphate. 

MEVALONATE KINASE MYOSIN and MYOSIN ATPase NAD KINASE NAD SYNTHETASE... 

MYOSIN and MYOSIN ATPase NAD SYNTHETASE 3 -NUCLEOTIDASE 5 -NUCLEOTIDASE... 

FlexXd used for docking a library of >19,000 ViChemg compounds and Tripos Leadquest compounds into NAD synthetase PknB... 

Nine submicromolar inhibitors were found. Additional further docking for NAD kinase inhibitors found that 22 showed activity versus NAD synthetase and one against NAD kinase out of 100 compounds tested... 

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. ... 

Figure 11.9. ISAD synthesis pathway from nicotinamide or niacin (l)nicoti-namidase (E.C. 3.5.1.19) (2)nicotinamide phosphoribosyl transferase, which requires ATP (3)1SIMN adenyl transferase, which requires ATP (4) nicotinic acid phosphoribosyl transferase, which requires ATP (5) NMN adenyl transferase, which requires ATP (6) NAD synthetase, which requires ATP. Ri, ribose P, phosphate Ad, adenine NMN, nicotinamide mononucleotide. This figure is from Ref 33 and is used with permission.

Yamaguchi F, Etoh T, Takahashi M, Misaki H, Sakuraba H, Ohshiraa T. A new enzymatic cycling method for ammonia assay using NAD synthetase. Clin Chim Acta 2005 352 165-73. 

Traditionally, this reaction was assumed to occur only at the level of a dinucleotide intermediate NaAD catalyzed by the enzyme NAD synthetase (NADSYN). However, it was recently shown that at least some members of the same enzyme family possess an unusual NMN synthetase activity (NMNSYN) efficiently catalyzing amidation of a mononucleotide intermediate NaMN. As mentioned earlier, NMNSYN together... 

Azaserine, a glutamine antagonist," is known to inhibit the NAD synthetase reaction in which nicotinic acid adenine dinucleotide is converted into NAD with glutamine or ammonia as the nitrogen donor. ° When azaserine or azaleucine was fed to Ricinus communis plants followed by [6- C]quinolinic acid, a marked decrease in incorporation of radioactivity into ricinine was observed with azaleucine, less so with azaserine." Both azaserine and azaleucine were found also to inhibit the incorporation of [6- " C]quinolinic acid into pyridine nucleotide cycle intermediates [in the case of azaserine the conversion of nicotinic acid dinucleotide into nicotinamide adenine dinucleotide (NAD ) was apparently inhibited]. 

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. 

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. 

Figure 2 NAD metabolism. Tip = tryptophan, 3-HK = 3-hydroxykynurenine, 3-HA = 3-hydroxyanthranilic acid, ACMS = a-amino-P-carboxymuconate- -semialdehyde, AMS = a-aminomuconate- -semialdehyde, NaMN = nicotinic acid mononucleotide, NMN = nicotinamide mononucleotide, NaAD = nicotinic acid adenine dinucleotide. For other abbreviations, see Figure 1. (1) tryptophan oxygenase [EC 1.13.11.11], (2) formy-dase [EC 3.5.1.9], (3) kynurenine 3-hydroxylase [EC 1.14.13.9], (4) kynureninase [EC 3.7.1.3], (5) 3-hydroxyanthranilic acid oxygenase [EC 1.13.11.6], (6) nonenzymatic, (7) aminocarboxymuconate-semialdehyde decarboxylase [EC 4.1.1.45], (8) quinolinate phos-phoribosyltransferase [EC 2.4.2.19], (9) NaMN adenylyltransferase [EC 2.7.2.18], (10) NAD synthetase [EC 6.3.5.1], (11) NAD kinase [EC 2.7.1.23], (12) NAD" glycohydro-lase [EC 3.2.2.5], (13) nicotinamide methyltransferase [EC 2.2.1.1], (14) 2-Py-forming MNA oxidase [EC 1.2.3.1], (15) 4-Py-forming MNA oxidase [EC number not given], (16) nicotinamide phosphoribosyltransferase [EC 2.4.2.12], (17) NMN adenylytransferase [EC 2.7.71], (18) nicotinate phosphoribosyltransferase [EC 2.4.2.11], (19) nicotinate methyltransferase [EC 2.7.1.7], and nicotinamidase [EC 3.5.1.19]. Solid line, biosynthesis dotted line, catabolism.

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