Nicotinamide coenzyme from nicotinic acid

Two coenzymes which are involved in most of the redox reactions of metabolism are nicotine adenine dinucleotide, NAD", and FAD, flavine adenine dinucleotide. Most metabolic oxidations are, in fact, dehydrogenations, and not reactions with oxygen. Nicotinamide is derived from nicotinic acid, and the isoalloxazine ring of FAD is derived from riboflavin. Thiamin is the principal cofactor in enzymatic decarboxylations. Many of the vitamins serve as coenzymes in a wide variety of cellular reactions. 

Aicotinic acid derivatives Nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP-) (D 16.2) Coenzymes and cosubstrates of oxido-reductases (C 2.1), in humans synthesized from nicotinic acid and nicotinamide. Both substances belong to the vitamin B complex... 

Most foods of animal origin contain nicotinamide in the coenzyme form (high bioavialability). Liver and meat are particularly rich in highly bioavailable niacin. Most of the niacin in plants, however, occurs as nicotinic acid in overall lower concentrations and with a lower bioavailability. The major portion of niacin in cereals is found in the outer layer and its bioavailability is as low as 30% because it is bound to protein (niacytin). If the diet contains a surplus of L-tryptophan (Ttp), e.g., more than is necessary for protein synthesis, the liver can synthesize NAD from Trp. Niacin requirements are therefore declared as niacin equivalents (1 NE = 1 mg niacin = 60 mg Trp). 

Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions (Figure 45-11). About 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as mg niacin equivalents = mg preformed niacin + 1/60 X mg tryptophan. Because most of the niacin in cereals is biologically unavailable, this is discounted. 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

The biological importance of these compounds stems from their use as cofactors. Both nicotinamide and nicotinic acid are building blocks for coenzyme I (Co I), nicotinarnide—adenine dinucleotide (NAD) (3) and coenzyme 11 (Co II), nicotinamide—adenine dinudeotide phosphate (NADP) (4) (2). 

Nicotinic acid (niacin) was prepared first by oxidation of the alkaloid nicotine, but nut until 1913 was it isolated from yeast and recognized as an essential food factor (see tlu structures). In 1934-1935, nicotinamide was obtained from the hydrolysis of a coenzyme isolated from horse red blood cells. This coenzyme was later named coenzyme II and is now more commonly called nicolinainide adenine dinuclen-tide pho.iphate (NADP). 

Niacin (nicotinic acid pyridine-3-carboxylic acid) and nicotinamide are precursors of NAD+ and NADP+ (Figure 38-19). Niacin occurs in meat, eggs, yeast, and whole-grain cereals in conjunction with other members of the vitamin B group. Little is known about absorption, transport, and excretion of niacin and its coenzyme forms. A limited amount of niacin can be synthesized in the body from tryptophan, but it is not adequate to meet metabolic needs. 

In the first stage of respiration, a six-carbon glucose molecule is split into a pair of three-carbon molecules. Hydrogen Ions and electrons also are produced in glycolysis. These combine with electron carrier ions called nicotinamide adenine dinucleotide (NAD+) to form NADH. NADH is a coenzyme that is made from vitamin B4, which is also called niacin or nicotinic acid. ATP and NADH serve as temporary storage sites for energy and electrons, respectively, during respiration. Two molecules of ATP are used, and four molecules are produced. ... 

Nicotinic acid (niacin) is a precursor of nicotinamide adenine dinucleotide (NAD) which plays a central role in metabolism as a coenzyme. It can be synthesized from tryptophan. Tryptophan and nicotinate deficiency lead to pellagra, which is characterized by diarrhea, dermatitis, and dementia. Maize-rich diets... 

N-(2-hydroxyethyl)-nicotinamide, which undergoes further side-chain degradation to nicotinuric acid and, subsequently, nicotinamide and nicotinamide metabolites (e.g., nicotinic acid and N-methylnicotinamide). The nicotinamide derived from nicorandil merges into the endogenous pool of nicotinamide adenine dinucleoside coenzymes. Its elimination half-life is approximately 1 hour. Approximately 30% of nicorandil is excreted into the urine as metabolites, with less than 1% excreted unchanged. 

Nicotinic acid is a B-complex vitamin that is converted to nicotinamide, NAD, and NADP. The latter two compounds are coenzymes and are required tor oxidation/reduction reactions in a variety of biochemical pathways. Additionally, nicotinic acid is metabolized to a number of inactive compounds, including nicotinuric acid and N-methylated derivatives. Normal biochemical regulation and feedback prevent large doses of nicotinic acid from producing excess quantities of NAD and NADP. Thus, small doses of nicotinic acid, such as those used tor dietary supplementation, will be primarily excreted as metabolites, whereas large doses, such as those used tor the treatment of hyperlipoproteinemia, will be primarily excreted unchanged by the kidney (15). 

Nicotinic acid (niacin) and various nicotinamides are sources of the coenzyme nicotinamide adenine dinucleotide, synthesized in the mitochondria and vital for oxidative energy production in many metabolic reactions. The RDA is 15-20 mg, normally acquired from a balanced diet of meat, fish, whole cereals and yeast. Peas, beans, nuts, fruit and vegetables are all good sources of this vitamin. 

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. 

A member of the water-soluble B group of vitamins. It can be obtained from thediet orit can be synthesized endogenouslyfrom nicotinic acid, which is itself derived from tryptophan. Nicotinamide is a constituent of the coenzymes NAD and N ADP which have widespread roles in intermediary metabolism. Deficiency of the vitamins causes pellagra. Patients with Hart-nup s disease can develop a pellagra type condition probably due to insufficient endogenous synthesis of the vitamin from tryptophan. 

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). 

The formation of nicotinic acid, as important as it is for the synthesis of the two coenzymes nicotinamide-adenine dinucleotide and its phosphate (formulas in Chapt. VI-4), seems to be only a sidepath. The main degradation probably passes from the unstable, unsaturated aminoaldehyde through isomerization to the imino compound and through hydrolysis to the k to compound. The jS-decarboxylation of the latter results in an a-keto aldehyde with six C atoms which is further broken down to glutarate. 

Preformed niacin occurs in foods either as nicotinamide (niacinamide) or as the pyridine nucleotide coenzymes derived from it, or as nicotinic acid, without the amide nitrogen, which is the form known as niacin in North America. Both nicotinamide and nicotinic acid are equally effective as the vitamin, but in large doses they exert markedly different pharmacological effects, so it is important, at least in that context, to make and maintain the distinction. In addition to the preformed vitamin, an important in vivo precursor is the amino acid L-tryptophan, obtained from dietary protein. Because the human total niacin supply, and hence niacin status, depends on the dietary tryptophan supply as well as on the amount of preformed dietary niacin and its bioavailability, it has become the accepted practice to express niacin intakes as niacin equivalents, ... 

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. 

When examined by following oxygen uptake the effects of different derivatives of nicotinic acid were not straightforward. Though nicotinamide was more active than nicotinic acid, cozymase was less active than nicotinamide. This observation, initially based on a comparison of nicotinamide with a specimen of cozymase estimated to be 40% pure, was confirmed by showing the activity of such a preparation, and also one of coenzyme II, to be increased on hydrolysis by autoclaving with 0.1 JV sulfuric acid. Conclusions drawn from these findings are discussed below. 

Whatever the explanation of the lesser activities of the coenzymes, the observation that their lesser activity in growth parallels that found in their metabolic stimulation is of value in emphasizing that the two processes are closely interdependent. A further correlation of this type is afforded by the observation (47) that nicotinic acid is unable to replace nicotinamide, both in growth and in hydrogen transport (from glucose to methylene blue), by PasteureUa suiseptica. The acid can replace the amide in both activities in related organisms (102). 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

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