Nicotinamide adenine dinucleotide catabolism

Nicotinamide is an essential part of two important coenzymes nicotinamide adenine dinucleotide (NAD ) and nicotinamide adenine dinucleotide phosphate (NADP ) (Figure 18.19). The reduced forms of these coenzymes are NADH and NADPH. The nieotinamide eoenzymes (also known as pyridine nucleotides) are electron carriers. They play vital roles in a variety of enzyme-catalyzed oxidation-reduction reactions. (NAD is an electron acceptor in oxidative (catabolic) pathways and NADPH is an electron donor in reductive (biosynthetic) pathways.) These reactions involve direct transfer of hydride anion either to NAD(P) or from NAD(P)H. The enzymes that facilitate such... 

Endogenous NO is produced almost exclusively by L-arginine catabolism to L-citrul-line in a reaction catalyzed by a family of nitric oxide synthases (NOSs) [3]. In the first step, Arg is hydroxylated to an enzyme-bound intermediate "-hydroxy-1.-arginine (NHA), and 1 mol of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and O2 are consumed. In the second step, N H A is oxidized to citrulline and NO, with consumption of 0.5 mol of NADPH and 1 mol of 02 (Scheme 1.1). Oxygen activation in both steps is carried out by the enzyme-bound heme, which derives electrons from NADPH. Mammalian NOS consists of an N-terminal oxy-... 

Two important implications of the reactions described in Equations (5.1) and (5.2) are (i) that redox reactions play an important role in metabolic transformations, with the cofactors nicotinamide adenine dinucleotide (NAD+) acting as electron acceptor in catabolic pathways and nicotinamide adenine dinucleotide phosphate (NADPH) as electron donor in anabolism, and (ii) that energy must be produced by catabolism and used in biosyntheses (almost always in the form of adenosine triphosphate, ATP). 

The nicotinamide coenzymes nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH) are associated with a wide variety of enzymes involved in oxidation-reduction reactions (Fig. 21). NADH is typically involved in oxidative catabolic reactions, while NADPH is primarily used in biosynthetic pathways [58]. 

In contrast to plant cells, which normally get their cellular energy from photosynthesis, animal cells need a carbohydrate source, usually glucose, and the amino acid glutamine. The catabolism of these substrates allows the production of two coenzymes (ATP and NADH - nicotinamide adenine dinucleotide), which are essential for maintaining the viability of the cells. These coenzymes can be used for the maintenance, metabolism and/or for the synthesis of particular desired products (Wagner, 1997). 

Nicotinamide adenine dinucleotide is a coenzyme which is only loosely bound to the active site of the enzymes with which it interacts and is free therefore, to dissociate from the enzyme during the catalytic cycle. The role of the dehydrogenase enzyme is to bring together the substrate and the NAD+ in the correct orientation for the two to react. These NAD+-dependent enzymes are known as dehydrogenases. They work in conjunction with NAD+ to oxidise substrates by the transfer of 1H+ and 2e from the substrate to the 4-position of the nicotinamide ring of the NAD+ (see Fig. 2.1). The overall reaction is the equivalent of a hydride transfer and is commonly referred to as such. NAD+-dependent enzymes are primarily involved in respiration (NAD+ occurs in significant amounts in mitochondria), whereas, NADP+-dependent coenzymes are primarily involved in the transfer of electrons from intermediates in catabolism. 

NAD+ Oxidized form of nicotinamide adenine dinucleotide. Note that despite the plus sign in the symbol, the coenzyme is anionic under normal physiological conditions. NAD+ is a coenzyme derived from the B vitamin niacin. It is transformed into NADH when it accepts a pair of high-energy electrons for transport in cells and is associated with catabolic and energy-yielding reactions. 

Aune and Pogue344 presented data indicating that at least two distinct mechanisms, (1) stimulation of cellular catabolism of tryptophan and (2) stimulation of cellular catabolism of nicotinamide adenine dinucleotide (NAD) by adenosine diphosphate-ritosyl transferase (ADP-RT), can account for IFN-y-mediated inhibition of tumor cell growth. Both mechanisms appear to be sensitive to oxygen tension and to changes in intracellular glutathione concentrations, and both mechanisms lead to loss of intracellular NAD. 

The relationship between anabolic and catabolic processes is illustrated in Figure 1.20. As nutrient molecules are degraded, energy and reducing power are conserved in ATP and NADH molecules, respectively. Biosynthetic processes use metabolites of catabolism, synthesized ATP and NADPH (reduced nicotinamide adenine dinucleotide phosphate, a source of reducing power, i.e., high-energy electrons), to create complex structure and function. 

In contrast to our understanding of the biosynthesis of cofactors, relatively little is known about cofactor degradation. Some previous research has been carried out to identify intermediates on these catabolic pathways, but very little information is available on the genes involved and on the enzymol-ogy. In this chapter we summarize our current understanding of the pyridoxal phosphate, riboflavin, heme, thiamin, biotin, nicotinamide adenine dinucleotide (NAD), folate, lipoate, and coenzyme A catabolic pathways in all life-forms and discuss mechanistic aspects of the most interesting catabolic reactions. 

Nicotinamide adenine dinucleotide (NAD) is the coenzyme form of the vitamin niacin. Most biochemical reactions require protein catalysts (enzymes). Some enzymes, lysozyme or trypsin, for example, catalyze reactions by themselves, but many require helper substances such as coenzymes, metal ions, and ribonucleic acid (RNA). Niacin is a component of two coenzymes NAD, and nicotinamide adenine dinucleotide phosphate (N/kDP). NAD (the oxidized form of the NAD coenzyme) is important in catabolism and in the production of metabolic energy. NADP (the oxidized form of NADP) is important in the biosynthesis of fats and sugars. 

The electron donor in most reductive biosyntheses is NADPH, the reduced form of nicotinamide adenine dinucleotide phosphate (NADP see Figure 14.13). NADPH differs from NADH in that the 2 -hydroxyl group of its adenosine moiety is esterified with phosphate. NADPH carries electrons in the same way as NADH. However, NADPH is used almost exclusively for reductive biosyntheses, whereas NADH is used primarily for the generation of ATP. The extra phosphoryl group on NADPH is a tag that enables enzymes to distinguish between high-potential electrons to be used in anabolism and those to be used in catabolism. 

During oxidation, hydrogen ions (protons) and electrons are removed from fuel molecules and transferred to one of a small number of special carrier molecules. The most abundant such molecule is nicotinamide adenine dinucleotide (NAD+). It forms an essential link between the oxidative part of catabolism and the generation of ATP. 

Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that acts as a hydrogen acceptor. Many types of dehydrogenases remove electrons from their snbstrates and reduce NAD+ into NADH. This reduced form of the coenzyme then serves as a snbstrate for any of the reductases in the cell that need to reduce their substrates. Nicotinamide adenine dinncleotide exists in two related forms in the cell NADH and NADPH. The NAD+/NADH is nsed in catabolic reactions, while NADP/NADPH is used in anabolic reactions. 

Oxidative reactions in catabolic sequences involve the removal of electrons from an intermediate. This process is controlled by dehydrogenases and often involves the participation of the cofactor nicotinamide adenine dinucleotide (NAD or NAD+). Electrons from the donor are transferred to NAD in the form of the hydride ion [ H-] to produce reduced NAD (NADH). In many reactions two hydrogen atoms are removed from the substrate, one in the form of the hydride ion, the other liberated as a proton accordingly, the reduction of NAD+ is often written as... 

Anabolic (biosynthetic) reactions are driven by ATP energy, and the process of reduction is mediated by enzymes most of which utilize nicotinamide adenine dinucleotide phosphate (NADP or NADP+) as cofactor. The specificity of catabolism for NAD+ and anabolism for NADP+ is an example of chemical compartmentation and enables some degree of metabolic regulation to be exerted through control of the levels of the two cofactors. The relative concentrations of the oxidized and reduced forms of a particular cofactor may also serve a regulatory role. 

Whereas catabolism involves oxidation of starting molecnles, biosynthesis or anabolism involves reduction reactions, hence the need for a reducing agent or hydrogen donor, which is usually NADP (nicotinamide adenine dinucleotide phosphate). These catalysts are known as coenzymes and the most widely occurring is coenzyme A (CoA), made up of ADP (adenosine diphosphate) and pantetheine phosphate. 

Tang JCT, Ruch EE, Lin ECC (1979) Purification and properties of a nicotinamide adenine dinucleotide-linked dehydrogenase that serves an Escherichia coli mutant for glycerol catabolism. J Bacteriol 140 182—187 Tang JCT, Forage RG, Lin ECC (1982) Immunochemical properties of NAD -linked glycerol dehydrogenases from Escherichia coli and Klebsiella pneumoniae. J Bacteriol 152 1169—1174... 

NAD (nicotinamide adenine dinucleotide) An oxidized coenzyme used in catabolic reactions. 

The pentose phosphate pathway is also known as the hexose monophosphate shunt and the phos-phogluconate pathway because of the variety of intermediates formed by the pathway under different conditons. The pathway which occurs in a wide variety of organisms including animals, plants and microorganisms is classihable as secondary metabolism (Section 10.5) due to the relatively small quantity of glucose catabolized by this route. In mammalian tissues, the pathway yields a number of important products, in particular, reduced nicotinamide adenine dinucleotide phosphate (NADPH) and pentose sugars. 

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