Nicotinamide adenine dinucleotide phosphate metabolic function

The most important product of the hexose monophosphate pathway is reduced nicotinamide-adenine dinucleotide phosphate (NADPH). Another important function of this pathway is to provide ribose for nucleic acid synthesis. In the red blood cell, NADPH is a major reducing agent and serves as a cofactor in the reduction of oxidized glutathione, thereby protecting the cell against oxidative attack. In the syndromes associated with dysfunction of the hexose monophosphate pathway and glutathione metabolism and synthesis, oxidative denaturation of hemoglobin is the major contributor to the hemolytic process. 

Hexachloroethane is metabolized by the mixed function oxidase system by way of a two-step reduction reaction involving cytochrome P-450 and either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or cytochrome b5 as an electron donor. The first step of the reduction reaction results in the formation of the pentachloroethyl free radical. In the second step, tetrachloroethene is formed as the primary metabolite. Two chloride ions are released. Pentachloroethane is a minor metabolic product that is generated from the pentachloroethyl free radical. 

Niacin is also known as vitamin PP or vitamin Bj. The term niacin describes two related compounds, nicotinic acid and nicotinamide (Figure 19.18), both with biological activity. Niacin is formed from the metabolism of tryptophan, and therefore it is not strictly a vitamin. It is a precursor of two cofactors nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for the functioning of a wide range of enzymes involved in redox reactions. 

Niacin is a generic term which refers to two related chemical compounds, nicotinic acid (6.22) and its amide, nicotinamide (6.23) both are derivatives of pyridine. Nicotinic acid is synthesized chemically and can be easily converted to the amide in which form it is found in the body. Niacin is obtained from food or can be synthesized from tryptophan (60 mg of dietary tryptophan has the same metabolic effect as 1 mg niacin). Niacin forms part of two important co-enzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are co-factors for many enzymes that participate in various metabolic pathways and function in electron transport. 

Enzymes responsible for metabolism are located at various subcellular sites, for example the cytosol, mitochondria and smooth endoplasmic reticulum. However, it is enzymes derived from endoplasmic reticulum, called mixed function oxidases or monooxygenases , which have been most intensely studied in the past two or three decades. These enzyme systems, which utilize a family of haemoprotein cytochromes, or P-450 as terminal oxidases, require molecular oxygen and reduced nicotinamide adenine dinucleotide phosphate (NADPH) for activity. The overall stoichiometry of the reactions catalyzed by these enzymes is normally represented by equation (1). 

Niacin is unusual among the vitamins in that it was discovered as a chemical compound, nicotinic acid produced by the oxidation of nicotine, in 1867 -long before there was any suspicion that it might have a role in nutrition. Its metabolic function as part of what was then called coenzyme II [nicotinamide adenine dinucleotide phosphate (NADP)] was discovered in 1935, again before its nutritional significance was known. 

Phase I metabolism Phase I reactions (mainly oxidation, reduction, and hydrolysis) act as a preparation of the drug for the phase II reactions, i.e., a chemically reactive group is produced or uncovered on which the phase II reactions can occur, e.g., -OH, -NH2, -SH, -COOH. Most toxic metabolites are produced by phase I reactions. The P-450 isoenzymes (CYP enzymes), known collectively as the mixed function oxidase system, are found in the endoplasmic reticulum of many cells (notably those of liver, kidney, lung, and intestine) and perform many of these different functionalization reactions. The system requires the presence of molecular oxygen and co-factor nicotinamide adenine dinucleotide phosphate (NADPH) as well as cytochrome P450, NADPH-cytochrome P450 reductase, and lipid. 

Nicotinamide functions in the animal body as the active group of two important coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).These coenzymes are involved in the mechanism of hydrogen transfer in living cells (see Chapter 9) NAD is involved in the oxidative phosphorylation system, the tricyclic acid (TCA) cycle and the metabolism of many molecules, including pyruvate, acetate, (3-hydroxy-butyrate, glycerol, fatty acids and glutamate NADPH is the hydrogen acceptor in the pentose phosphate pathway. 

Figure 47.1 Intracellular metabolism of vitamin Bi2- Cyanocobalamin is first converted into cob(II)alamin, which has no cyanogen group on the ligand occupying the upper axial position of the cobalamin structure. Cob(II)alamin is further reduced to cob(I)alamin, which can function as a coenzyme in the body. Removal of a cyanide molecule from cyanocobalamin is directly reduced by NADPH and flavoprotein in the presence of a cyanocobalamin trafficking chaperone. Cobalamin is reportedly converted into its inactive form, cob(H)alamin, under oxidative stress (Lemer-Ellis et al. 2006). NADPH nicotinamide adenine dinucleotide phosphate.

The first examples of mechanism must be divided into two principal classes the chemistry of enzymes that require coenzymes, and that of enzymes without cofactors. The first class includes the enzymes of amino-acid metabolism that use pyridoxal phosphate, the oxidation-reduction enzymes that require nicotinamide adenine dinucleotides for activity, and enzymes that require thiamin or biotin. The second class includes the serine esterases and peptidases, some enzymes of sugar metabolism, enzymes that function by way of enamines as intermediates, and ribonuclease. An understanding of the mechanisms for all of these was well underway, although not completed, before 1963. 

Niacin is a water-soluble vitamin. The RDA of niacin for the adult man is 19 mg. Niacin is converted in the bi>dy to the cofactor nicotinamide adenine dinucleotide (NAD). NAD also exists in a phosphorylated form, NADP The phosphate group occurs on the 2-hydrr>xyl group of the AMP half of the coenzyme, NAD and NADP are used in the catalysis of oxidation and reduction reactions. These reactions are called redox reactions. NAD cycles between the oxidized form, NAD, and the reduced form, NADH + H. The coenzyme functions to accept and donate electrons. NADP behaves in a similar fashion. It occurs as NADP and NADPH + HT The utilization of NAD is illustrated in the sections on glycolysis, the malatc-aspartate shuttle, ketone body metabolism, and fatty acid oxidation. The utilization of NADP is illustrated in the sectirrns concerning fatty acid synthesis and the pentose phosphate pathway. 

Other important energy carriers in metabolism are nicotinamide adenine dinucleotide (NAD+), and the closely related nicotinamide dinucleotide phosphate (NADP), which transport electrons rather than whole groups (11.23). NADPH, like ATP, functions as a source of free energy for various biosynthetic reactions. 

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