Nicotinamide redox functions

NAD+ possesses some non-redox functions as well. The glycosidic linkage between nicotinamide and ribose is a high-energy bond. The energy provided by... 

Why are there two pyridine nucleotides, NAD+ and NADP+, differing only in the presence or absence of an extra phosphate group One important answer is that they are members of two different oxidation-reduction systems, both based on nicotinamide but functionally independent. The experimentally measured ratio [NAD+] / [NADH] is much higher than the ratio [NADP+] / [NADPH]. Thus, these two coenzyme systems also can operate within a cell at different redox potentials. A related generalization that holds much of the time is that NAD+ is usually involved in pathways of catabolism, where it functions as an oxidant, while NADPH is more often used as a reducing agent in biosynthetic processes. See Chapter 17, Section I for further discussion. 

Figure 8.5. Redox function of the nicotinamide nucleotide coenzymes.

Figure 1.9 Examples of functionally important intrinsic metal atoms in proteins, (a) The di-iron center of the enzyme ribonucleotide reductase. Two iron atoms form a redox center that produces a free radical in a nearby tyrosine side chain. The iron atoms are bridged by a glutamic acid residue and a negatively charged oxygen atom called a p-oxo bridge. The coordination of the iron atoms is completed by histidine, aspartic acid, and glutamic acid side chains as well as water molecules, (b) The catalytically active zinc atom in the enzyme alcohol dehydrogenase. The zinc atom is coordinated to the protein by one histidine and two cysteine side chains. During catalysis zinc binds an alcohol molecule in a suitable position for hydride transfer to the coenzyme moiety, a nicotinamide, [(a) Adapted from P. Nordlund et al., Nature 345 593-598, 1990.)...

Dehydrogenases, which represent a majority of redox enzymes, are mostly NAD (Nicotinamide Adenine Dinucleotide, see Fig. 12.9) dependent. This cofactor is not directly bound to the enzyme but its presence in the medium is necessary because it acts as a carrier of two electrons and one proton, and it activates the biocatalytic function of the enzyme. 

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. 

NAD+ (structure 8.11, R = H) and NADP+ (structure 8.11, R = P03 ) function as coenzymes in redox reactions by reversibly accepting hydrogen at the 4 position of the nicotinamide ring (equation 8.12). 

Several of the B vitamins function as coenzymes or as precursors of coenzymes some of these have been mentioned previously. Nicotinamide adenine dinucleotide (NAD) which, in conjunction with the enzyme alcohol dehydrogenase, oxidizes ethanol to ethanal (Section 15-6C), also is the oxidant in the citric acid cycle (Section 20-10B). The precursor to NAD is the B vitamin, niacin or nicotinic acid (Section 23-2). Riboflavin (vitamin B2) is a precursor of flavin adenine nucleotide FAD, a coenzyme in redox processes rather like NAD (Section 15-6C). Another example of a coenzyme is pyri-doxal (vitamin B6), mentioned in connection with the deamination and decarboxylation of amino acids (Section 25-5C). Yet another is coenzyme A (CoASH), which is essential for metabolism and biosynthesis (Sections 18-8F, 20-10B, and 30-5A). 

The nicotinamide nucleotide coenzymes function as electron carriers in a wide variety of redox reactions. In addition, NAD is the precursor of adenine dinucleotide phosphate (ADP)-ribose for ADP-ribosylation and poly(ADP-ribosylation) of proteins and cADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). They act as second messengers and stimulate increases in intracellular calcium concentrations. 

Several enzymes such as reductases and dehydrogenases utilize nicotinamide derivatives as reversible carriers of redox equivalents. The reduced dihydronicotinamide moiety NAD(P)H acts by donating a hydride equivalent to other molecules. In the corresponding two-electron oxidized NAD(P) form, the cofactor formally accepts a hydride ion from the substrate. Functional models of such reversible hydride transfer processes are of considerable interest for biomimetic chemistry, and the strategies to regenerate nicotinamide-type cofactors are crucial for the performance of many organic transformations involving biocatalytic key steps 139,140). 

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. 

If we accept that the redox state of nicotinamide nucleotides is a modulating system, we need to know how this works. An attractive idea involves the fact that the NADPH/NADP+ ratio is in equilibrium with the GSH/GSSG ratio which itself is of importance for the redox state and therefore the activity of functional proteins (Barron, 1951). 

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