Perspectives in Pharmacology NAD and Vitamin B3: From Metabolism to Therapies

The role of NAD metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD metabolism regulates important biological effects, including lifespan. NAD exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADPribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD metabolism in humans and microbes, including new insights into mechanisms that regulate NAD biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD biosynthesis for treatment of human disorders and infections. Vitamin B3 (nicotinamide and nicotinic acid) is essential to all living cells. Vitamin B3 is biosynthetically converted to nicotinamide adenine dinucleotide (Fig. 1, NAD ), a versatile acceptor of hydride equivalents to form the reduced dinucleotide, NADH. The phosphorylated forms of the nicotinamide dinucleotides (NADP/NADPH) perform similar chemical functions within cells, although these are generally used in biosynthetic pathways and in cell protection mechanisms against reactive oxygen species. NAD(P)H provides reducing equivalents for cellular biochemistry and energy metabolism. Within eukaryotic cells, energy metabolism is largely mediated by electron transport chains found within the mitochondrion, and NADH plays a vital role in furnishing reducing equivalents to fuel oxidative phosphorylation. Thus, cellular energy metabolism is substantially mediated by vitamin B3derived cofactors, and a large fraction of anabolic and catabolic pathways incorporates these cofactors within them. Nicotinamide dinucleotides also react as electrophiles to transfer the ADP-ribose (ADPR) moiety to a nucleophile. ADPR transfer to small nucleophiles forms ADPR (nucleophile/water), cyclic-ADPR (nucleophile/N1 adenine), and nicotinic acid adenine dinucleotide-phosphate (derived from NADP , nucleophile/nicotinic acid). These compounds have been shown to regulate processes, such as channel opening and calcium release (Pollak et al., 2007). Furthermore, ADPR transfer modifies protein nucleophilic side chains (Hassa et al., 2006). The ADPR-transfer enzymes fall into three distinct families, the mono-ADP-ribosyltransferases (Hassa et al., 2006), the poly(ADP-ribosyl) polymerases (PARPs) (Virag and Szabo, 2002; Hassa et al., 2006), and the sirtuins (Sauve et al., 2006). The sirtuins transiently ADP-ribosylate acetyllysines of proteins causing protein deacetylation, releasing an acetyl transfer product, acetyl-ADP-ribose (Sauve et al., 2006). However, some sirtuins are not deacetylases and appear to catalyze protein ADPR transfer in the ordinary sense. This work has been supported in part by National Institutes of Health Grant DK 73466-01 (to A.S.). A.S. is a consultant for Sirtris Pharmaceuticals and has financial interests related to some of the topics discussed in this review. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.120758. ABBREVIATIONS: ADPR, adenosine diphosphate ribose; APP, amyloid precursor protein; NAMN, nicotinic acid mononucleotide; nampt, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; nmnat, nicotinamide/nicotinate mononucleotide adenylyltransferase; NR, nicotinamide riboside; PARP, poly(ADP-ribose) polymerase; PBEF, pre-B-cell colony-enhancing factor; PRPP, 5-phosphoryl-ribose1-pyrophosphate; QA, quinolinic acid; Sir2, silencing information regulator 2; HDL, high-density lipoprotein; SIRT1, mammalian sirtuin 1; FK-866, (E)-N-[4-(1-benzoylpiperidine-4-yl)butyl]-3-(pyridin-3-yl)acrylamide. 0022-3565/08/3243-883–893$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 324, No. 3 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 120758/3314072 JPET 324:883–893, 2008 Printed in U.S.A. 883 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from