Nicotinic Ribonucleotide

This enzyme [EC 2.7.7.1], also known as NAD pyropho-sphorylase, catalyzes the reaction of ATP with nicotinamide ribonucleotide to produce NAD+ and pyrophosphate (or, diphosphate). Nicotinate nucleotide is also a substrate. Nicotinate-nucleotide adenylyltransferase [EC 2.7.7.18] uses nicotinate ribonucleotide as the pyridine substrate, thereby producing deamido-NAD and pyrophosphate. 

An AMP moiety is transferred from ATP to nicotinate ribonucleotide to form desamido-NAD. The final step is the transfer of the ammonia generated from the amide group of glutamine to the nicotinate carboxyl group to form NAD+. 

PRPP is the activated intermediate in the synthesis of phosphoribosylamine in the de novo pathway of purine formation of purine nucleotides from free bases by the salvage pathway of orotidylate in the formation of pyrimidines of nicotinate ribonucleotide of phosphoribosyl ATP in the pathway leading to histidine and of phosphoribosylanthranilate in the pathway leading to tryptophan. 

The answer is a. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121—138. Wilson, pp 287-320.) The major contributor of electrons in reductive biosynthetic reactions is nicotinamide adenine dinucleotide phosphate (NADPH -I- H ), which is derived by reduction of NAD. NAD is formed from the vitamin niacin (also called nicotinate). Niacin can be formed from tryptophan in humans. In the synthesis of NAD, niacin reacts with 5-phosphoribosyl-l-pyrophosphate to form nicotinate ribonucleotide. Then, AMP is transferred from ATP to nicotinate ribonucleotide. Finally, the amide group of glutamate is transferred to the niacin carboxyl group to form the final product, NAD. NADP is derived from NAD by phosphorylation of the 2 -hydroxyl group of the adenine ribose moiety. The reduction of NADP to NADPH -I- H occurs primarily through the hexose monophosphate shunt. 

Scheme 13.18. An expansion of Scheme 12.103 allowing the formation of free nicotinic acid and ribose-5-phosphate from a nicotinate ribonucleotide. 

This enzyme [EC 2.4.2.21] catalyzes the reaction of /3-nicotinate D-ribonucleotide with dimethylbenzimidazole to produce nicotinate and Af -(5-phospho-a-D-ribosyl)-5,6-dimethylbenzimidazole. Benzimidazole also serves as a substrate. The clostridial enzyme acts on adenine to produce 7-a-D-ribosyladenine 5 -phosphate. 

This enzyme [EC 2.4.2.19], also referred to as nicotinate mononucleotide pyrophosphorylase (carboxylating), catalyzes the reversible reaction of pyridine 2,3-dicar-boxylate and 5-phospho-a-o-ribose 1-diphosphate to produce nicotinate D-ribonucleotide, carbon dioxide, and pyrophosphate. 

Conversion of nicotinic acid to NAD is illustrated by the following experiment involving mice (Figure 9.63), The animals were injected with carbon-14-labeled nicotinic acid. The livers were removed at the indicated times — 0.33,1.0,3.0, and 10 minutes — and used for analysis of the radioactive metabolites. At 20 seconds, unchanged nicotirric acid (O) w as the major metabolite. At 1 to 3 minutes, there was a temporary accumulation of nicotinic acid ribonucleotide (V) and deamjdo-NAD (A). NAD ( ) was the major metabolite after 3 minutes. 

As mentioned earlier, milk was often used to treat pellagra however, neither milk nor eggs contain very much niacin. The question arises How can milk reverse the symptoms of a disease known to result mainly from niacin deficiency The answer lies in a consideration of the pathway of catabolism of one of the amino acids, tryptophan. The breakdown of tryptophan may follow a number of different routes, including that shown in Figure 9.68. The final pniduct of this pathway is nicotinic acid ribonucleotide, which can be converted to NAD. A small fraction of... 

Nicotinamide-adenine dinucleotide (NAD diphosphopyri-dine nucleotide) and nicotinamide-adenine dinucleotide phosphate (NADP also termed triphosphopyridine nucleotide) represent most of the niacin activity found in good sources that include yeast, lean meats, liver, and poultry. Milk, canned salmon, and several leafy green vegetables contribute lesser amounts but are still sufficient to prevent deficiency. Additionally, some plant foodstuffs, especially cereals such as corn and wheat, contain niacin bound to various peptides and sugars in forms nutritionally not readily available (niacinogens or niacytin). Because tryptophan is a precursor of niacin, protein provides a considerable portion of niacin equivalent. As much as two thirds of niacin required by adults can be derived from tryptophan metaboHsm via nicotinic acid ribonucleotide... 

Little of the tryptophan that enters the tryptophan-niacin pathway is actually used to form nicotinie acid ribonucleotide, and 60 mg of tryptophan results in the formation of only about 1 mg of nicotinic add (C8). Evidence recently reviewed (C8) indicates that this ratio is not a fixed one and shows considerable variation depending upon the amount of tryptophan and preformed nicotinic acid available to the organism and also the amount of PLP present. It is also of interest that nicotinie acid in the form of NADPH is required in one enzymic step in the kynurenine pathway, the hydroxylation of kymurenine to 3-hydroxy k murenine. 

Biosynthesis Phosphoribose pyrophosphate + nicotinic acid - nicotinic acid ribonucleotide. Coupling with ATP under cleavage of diphosphate furnishes de-amido-NAD. The amide nitrogen originates from glutamine. 

Nicotinic acid ribonucleotide - - ATP — nicotinic acid adenine dinucleotide - - PPi... 

Carboxy-l-(5-0-phosphono-P-D-ribofur-anosyl)pyridinium hydroxide inner salt, 9CI. 3-Carboxy-l-P-D-ribofuranosylpyridi-nium hydroxide 5 -(dihydrogen phosphate) inner salt, SCI. Deamido-NMN. Niacin ribonucleotide. Nicotinic acid ribonucleotide... 

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... 

The conversion of nicotinamide to nicotinic acid requires the activities of a deaminase and a ribonucleotide pyrophosphorylase. Although a detailed description of mechanisms controlling NAD coenzyme synthesis in mammalian tissues is not available, it has been suggested that the regulatory restraints are... 

The free nicotinamide liberated in Eq. (10a) would be converted to DPN, hence giving a net synthesis of an additional mole of DPN. It is possible that pyridine-3-aldehyde and pyridyl-3-carbinol are poor precursors of DPN in comparison to the 3-CH3-pyridine, because they may be rapidly converted to nicotinic acid at the free base stage whereas the picoline derivative is not. Tryptophan conversion to nicotinamide may also occur with intermediates at the riboside, ribonucleotide, or dinucleotide stage. That such intermediates may exist is suggested by the studies of Yanofsky i09) who has obtained evidence for the synthesis of anthranilic acid ribonucleotide in E. colt. 

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