Metabolic functions of niacin Domina Petric MD Coenzyme

Metabolic functions of niacin Domina Petric, MD

Coenzyme functions • Niacin functions metabolically as the essential component of the enzyme co-substrates NAD(H) and NADP(H). The most central electron transport carriers of cells, each acts as an intermediate in most of the hydrogen transfers in metabolism, including more than 200 reactions in the metabolism of carbohydrates, fatty acids and amino acids according to the general reaction: • substrate + NAD(P)+ → product + NAD(P)H + H+ February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 2

Coenzyme functions • The hydrogen transport by the pyridine nucleotides is accomplished by two-electron transfers in which the hydride ion (H-) serves as a carrier for both electrons. • The transfer is stereospecific, involving C-4 of the pyridine ring. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 3

Coenzyme functions The two hydrogen atoms at C-4 of NAD(H) and NADP(H) are not equivalent. Each is stereospecifically transferred by the enzymes to the corresponding substrates. Stereospecificity is independent of the nature of the substrate and the source of the enzyme. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 4

Coenzyme functions The reactions catalyzed by the pyridine nucleotide dependent dehydrogenases occur by: • abstraction of the proton from the alcoholic hydroxyl group of the donor substrate • transfer of hydride ion from the same carbon atom to the C-4 of NAm In many cases, this reaction is coupled to a further reaction, such as phosphorylation or decarboxylation. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 5

Metabolic roles Despite their similarities of mechanism and structure, NAD(H) and NADP(H) have quite different metabolic roles and most dehydrogenases have specificity for one or the other. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 6

NAD in redox reactions The oxidized form NAD+ serves as a hydrogen acceptor at the C-4 position of the pyridine ring, forming NAD(H) which, in turn, functions as a hydrogen donor to the mitochondrial respiratory chain (TCA cycle) for ATP production. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 7

NAD in redox reactions Glycolytic reactions Oxidative decarboxylations of pyruvate Oxidation of acetate in the TCA cycle Oxidation of ethanol ß-oxidation of fatty acids Other cellular oxidations February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 8

NADP(H) in reduction reactions • The phosphorylation of NAD+ facilitates the separation of oxidation and reduction pathways of niacin cofactors by allowing NADP(H) to serve as a co-dehydrogenase in the oxidation of physiological fuels. • NADP(H) is maintained in the reduced state, NADPH by the pentose phosphate pathway such that reduction reactions are favored. • Many of these also involve flavoproteins. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 9

NADP(H) in reduction reactions These reactions involve reductive biosyntheses, such as those of fatty acids and steroids. NADPH also serves as a co-dehydrogenase for the oxidation of glucose 6 -phosphate in the pentose phosphate pathway. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 10

Genomic stability • The niacin metabolite NAD(H) functions in the post-translational modification of nuclear proteins by poly(ADP-ribose) polymerase. • This enzyme uses NAD+ as a direct substrate to provide the ribosyl moiety that is added to the receptor protein. • Poly-ADP-ribosylated proteins function in signal transduction by modulating the activities of G protein and p 53: role in DNA repair and replication, in cell differentiation and apoptosis. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 11

Glucose tolerance factor Niacin has been identified as part of the chromium containing glucose tolerance factor of yeast, which enhances the response to insulin. It is possible that this activity involves a metalchelating capacity of nicotinic acid such as has been reported for zinc and iron. February 13, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 12

Literature • Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. February 13, 2022 13