Synthesis of the Nicotinamide Nucleotide Coenzymes

In most extrahepatic tissues, nicotinic acid is a better precursor of nucleotides than is nicotintunide. However, muscle, brain, and to a lesser extent the testis are able to ttike up nicotintunide from the bloodstream effectively, and apparently utilize it without prior deamidation (Gerber and Deroo, 1970). 

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Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

It is not strictly correct to regard niacin as a vitamin. Its metabolic role is as the precursor of the nicotinamide moiety of the nicotinamide nucleotide coenzymes, nicotinamide adenine dinucleotide (NAD) and NADP, and this can also be synthesized in vivo from the essential amino acid tryptophan. At least in developed countries, average intakes of protein provide more than enough tryptophan to meet requirements for NAD synthesis without any need for preformed niacin. It is only when tryptophan metabolism is disturbed, or intake of the amino acid is inadequate, that niacin becomes a dietary essential. 

As shown in Figure 11.13, the nicotinamide nucleotide coenzymes can be synthesized from either of the niacin vitamers, and from quinolinic acid, an intermediate in the metabolism of tryptophan. In the liver, the oxidation of tryptophan results in a considerably greater synthesis of NAD than is required, and this is catabolized to release nicotinic acid and nicotinamide, which are taken up and used by other tissues for synthesis of the coenzymes. 

Of the two pyridine nucleotide coenzymes, NAD is present mainly as the oxidized form in the tissues, whereas NADP is principally present in the reduced form, NADPH2. There are important homeostatic regulation mechanisms which ensure and maintain an appropriate ratio of these coenzymes in then-respective oxidized or reduced forms in healthy tissues. Once converted to coenzymes within the cells, the niacin therein is effectively trapped, and can only diffuse out again after degradation to smaller molecules. This implies, of course, that the synthesis of the essential coenzyme nucleotides must occur within each tissue and cell type, each of which must possess the enzymatic apparatus for their synthesis from the precursor niacin. Loss of nicotinamide and nicotinic acid into the urine is minimized (except when the intake exceeds requirements) by means of an efficient reabsorption from the glomerular filtrate. 

Nucleotides are important constituents not only of RNA and DNA, but also of a number of key biomolecules considered many times in our study of biochemistry. NAD+ andNADP+, coenzymes that function in oxidation-reduction reactions, are metabolites of ATP. The first step in the synthesis of nicotinamide adenine dinucleotide (NAD+) is the formation of... 

The pentose phosphate pathway (PPP) is the major pathway for recycling nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and for the production of ribose-5-phosphate that is needed for the synthesis of nucleotides. The function of the PPP depends on the synthesis of nicotinamide-adenine dinucleotide phosphate (NADP) and thiamin pyrophosphate, a coenzyme... 

Purine and pyrimidine nucleotides are key components of all living cells on Earth, and are required for the synthesis of essential cofactors like the nicotinamide and flavine coenzymes and CoA as well as of vitamins like thiamin. Moreover, they are involved in the synthesis of secondary metabolites and are regulators of the synthesis... 

A considerable advance in elaborating the pathway of pyridine coenzyme synthesis resulted from the contributions of Preiss and Handler (118, 1B6-1B8). Before discussing the experiments of these investigators, it may be of value to review some of the earlier work on the metabolism of nicotinic acid and nicotinamide in erythrocytes. It has been known for some time that nicotinic acid taken orally results in a significant increase in the pyridine nucleotide content of human red blood cells (1B9, ISO). When equal concentrations of nicotinamide were given under identical conditions, there was no effect on the erythrocyte DPN level. Isolated erythrocytes have also been found to show a rise in DPN when incubated with nicotinic acid and not with nicotinamide. However, incubation with nicotinamide leads to a marked accumulation of nicotinamide mononucleotide (ISl). In this connection, it is of importance to point out that the level of the DPN pyrophosphorylase is extremely low in the red blood cell (ISB). 

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