and the Norris Cotton Cancer Center.pdf

Cell, Vol. 117, 495–502, May 14, 2004, Copyright ?2004 by Cell Press Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD
in Fungi and Humans (Maayan, 1964). In 2000, it became clear that Sir2 and Sir2-related enzymes termed Sirtuins deacetylate lysine residues with consumption of an equivalent of NAD
and that this activity is required for Sir2 function as a transcriptional silencer (Imai et al., 2000). It was also Pawel Bieganowski and Charles Brenner* Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center Dartmouth Medical School Rubin 733–HB7937 Lebanon, New Hampshire 03756 demonstrated that the Preiss-Handler pathway is re- quired for normal silencing activity in vivo (Smith et al., 2000). NAD
-dependent deacetylation reactions are re- quired not only for alterations in gene expression butSummary also for repression of ribosomal DNA recombination and extension of lifespan in response to calorie restrictionNAD
is essential for life in all organisms, both as a coenzyme for oxidoreductases and as a source of (Lin et al., 2000, 2002). NAD
is consumed by Sir2 to produce a mixture of 2- and 3 O-acetylated ADPriboseADPribosyl groups used in various reactions, including those that retard aging in experimental systems. Nico- plus nicotinamide and the deacetylated polypeptide (Sauve et al., 2001). Additional enzymes, including polytinic acid and nicotinamide were defined as the vitamin precursors of NAD
in Elvehjem’s classic discoveries (ADPribose) polymerases and cADPribose synthases are also NAD
-dependent and produce nicotinamideof the 1930s. The accepted view of eukaryotic NAD
biosynthesis, that all anabolism flows through nico- and ADPribosyl products (Ziegler, 2000; Burkle, 2001). Interest in the noncoenzymatic properties of NAD
tinic acid mononucleotide, was challenged experi- mentally and revealed that nicotinamide riboside is an has rekindled interest in NAD
b