Nicotinate phosphoribosyltransferase

Nicotinate phosphoribosyltransferase catalyzes the formation of nicotinate mononucleotide (NaMN) and pyrophosphate from 5-phosphoribosyl-a-D-pyrophosphate (PRibPP) and free nicotinic acid. The reaction requires the hydrolysis of ATP to ADP. 

The enzyme was purified from yeast and was free of N MN adenyltrans-ferase, ATPase, and adenylate kinase activities. 

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Figure 9.87 Elutions of the nicotinate phosphoribosyltransferase (N-PRTase) assay solution through a /xBondapak C18 column after various enzyme incubation times. The incubation mixture contained 5 mM MgCl2,100 y,M nicotinate, 75 tiM ATP, 30 /iM PRibPP, and 25 yu.L of 4 mg/mL N-PRTase in 50 mM Tris-HQ (pH 8). Elution conditions 5 yuL sample injection volumes, 0.7 mL/min flow rate, 25 m M (NH))P04 (pH 8) elution buffer, 25°C. (From Hanna and Sloan, 1980.)...

Quinolinatephosphoribosyltransferase(decarboxylating) 2 nicotinate mononucleotide adenylyl-transferase 3 nicotinamide adenine dinucleotide synthetase 4 NAD(P)+ nucleosidase 5 nicotin-amidase 6 nicotinate phosphoribosyltransferase... 

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.

Nicotinic acid, a pyridine compound, reacts with PP-ribose-P in the presence of nicotinate phosphoribosyltransferase (NPRT) to form nicotinic acid mononucleotide. The administration of nicotinic acid 1 gram to 5 patients was followed by a decrease in erythrocyte PP-ribose-P concentration to 25% of control values (Fig. 4). 

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.

Tarrant, J.M., Dhawan, P., Singh, J., Zabka, T.S., Clarke, E., DosSantos, E., Dragovich, P.S., Sampath, D., Lin, T., McCray, B., La, N., Nguyen, T., Kauss, A., Dambach, D., Misner, D.L., Diaz, D., Uppal, H. (2015). Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid. Toxicology Mechanisms and Methods, 25, 201-211. 

Diaz, D., and Uppal, H. (2015). PrecUnical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid. Toxicol Mech Methods 25(3), 201-211. 

Liang L, Liu R,Wang G, Gou D, Ma J, Chen K, et al. Regulation of NAD (H) pool and NADH/ NAD ratio by overexpression of nicotinic acid phosphoribosyltransferase for succinic acid production in Escherichia coli NZNlll. Enzyme Microbiol Technol 2012 51 286-93. 

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... 

Figure 7.3 NAD recycling. Humans have two metabolic pathways that are able to recycle nicotinamide. NAD-consuming enzymes (ARTs, PARPs, sirtuins) break down NAD to nicotinamide and ADP-ribosyl product. Nicotinamide by the enzymatic action of nicotinamide phosphoribosyltransferase (NAMP/PBEF) and nicotinamide/nicotinate-mononucleotide-adenyltransferases isoenzymes (NMATl-3) is then retransformed to NAD. In a second pathway, nicotinamide riboside is phosphorylated by nicotinamide riboside kinase (NRK 1,2) to nicotinamide mononucleotide. Subsequently, nicotinamide mononucleotide is converted to NAD by the catalytic action of NMNATs.

Scheme 12.103. Nicotinate nucleotide formed by the phosphoribosyltransferase quinolinate phosphoribosyltransferase (EC 2.4.2.19).

EC 2.7.7.1). The nicotinamide nucleotide itself can be produced with a phosphoribosyltransferase such as the quinolinate phosphoribosyltransferase (EC 2.4.2.19) (Scheme 12.103) to nicotinate ribonucleoide, which is subsequently converted to the amide. Other transferases, for example, EC 2.4.2.1, purinenucleoside phosphorylase, have also been implicated in the same process. It is generally assumed that phosphorylation of the carboxylate precedes amination and that a suitable source of nitrogen is found. Details remain unavailable at this writing. 

Quinolinic acid was identified as a metabolite of tryptophan in the rat by Henderson and Hirsch in 1949 (65). Quinolinic acid has been known to be a key intermediate of the tryptophan-NAD and aspartate + dihydroxyacetone phosphate-NAD pathways since the clear demonstration in vitro by Nishizuka and Hayaishi in 1963 (50). It has been proven that quinolinic acid is transformed into nicotinic acid mononucleotide in the presence of 5-phosphoribosyl-l-pyrophosphate by quinolinate phosphoribosyltransferase (50). In 1978 Lapin (52) first reported that quinolinic acid induced seizures when injected directly into the brains of mice. Later, quinolinic acid was shown to increase neuronal activity when ionophoreti-cally applied to neurons in rats cerebral cortex, striatum, and hippocampus (53,66,67). Now, quinolinic acid is known as a potent neurotoxin and as a precursor of NAD in the liver. 

Fig. 4. Effect of administration of drugs on intracellular phosphor-ibosylpyrophosphate (PP-ribose-P) levels in erythrocytes from patients with normal hypoxanthine-guanine phosphoribosyltransferase activity. Each point represents the mean value observed in the patients studied (expressed as percent of control Values) from 1 to 6 hours after drug administration, nicotinic acid (1 gram, 5 patients) orally, GHU nicotinamide (1 gram, 3 patients) orally,C>-0 fructose (0.5 mg/Kg, 4 patients) intravenously, — 2-deoxyglucose (50 mg/Kg, 1 patient) intravenously.

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