Structure Activities Of Antipedicular Agents

Niacin synthesis into the active cofactors, NAD+ and NADP+, is shown in Figure 28.29. Both niacin and niacinamide react with 5-phosphoribosyl-1-pyrophosphate (PRPP) to form the respective mononucleotide derivative, which then reacts with ATP to produce the corresponding dinucleotide product. For niacinamide, this is NAD + ; however, for niacin this product is converted to NAD+ by transformation of the carboxyl of the nico-tinic acid moiety to the amide using free ammonia. An alternative pathway is to use glutamine through NAD + synthase (glutamine-hydrolysing) (EC 6.3.5.1); however, this pathway is slower and is most likely not as important. NADP+ is produced from NAD+ by ATP through kinase catalysis.

Figure 28.29 • Biosynthesis of NAD+ and NADP+ from niacin, nicotinamide, or tryptophan.

NAD+ and NADP+ are oxidizing coenzymes for many (>200) dehydrogenases. Some dehydrogenases require NAD + , others require NADP+, and some function with either. The generalized representation in Figure 28.30 illustrates the function of these coenzymes in metabolic oxidations and reductions. The abbreviation NAD+ emphasizes the electrophilicity of the pyridine C4 moiety (which is the center of reactivity), and the substrate designated could be a

Substrate Coenzyme Product Reduced

(Alcohol) (Aldehyde/ketone) Coenzyme

Figure 28.30 • Generalized representation of the hydride transfer reaction.

Substrate Coenzyme Product Reduced

(Alcohol) (Aldehyde/ketone) Coenzyme

Figure 28.30 • Generalized representation of the hydride transfer reaction.

primary or secondary alcohol. Arrow a in Figure 28.30 symbolizes the function of NAD+ as oxidant in the hydride transfer from the substrate to the coenzyme, forming NADH, reduced coenzyme. The hydroxyl of the substrate is visualized as undergoing deprotonation concertedly by either water or the pyridine nitrogen of NADH. Arrow b shows concerted formation of the carbonyl ^-bond of the oxidation product. Arrow c symbolizes the reverse hydride transfer from reduced coenzyme, NADH, to the carbonyl carbon, and concertedly, as the carbonyl oxygen undergoes protonation, the reduction of the carbonyl group forms the corresponding alcohol. Thus, NAD+ and NADP+ are hydride acceptors, and NADH and NADPH are hydride donors. Although this is a simplistic representation, it shows the dynamism of the oxidation-reduction reactions effected by these coenzymes under appropriate dehydrogenase catalysis. Alternatively, the reduced coenzymes may be used in ATP production through the electron-transport system.

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