|
BMC Chemical Biology 2010
NAD+ metabolite levels as a function of vitamins and calorie restriction: evidence for different mechanisms of longevityAbstract: Hydrophilic interaction chromatography followed by tandem electrospray mass spectrometry were used to identify the 12 compounds that constitute the core NAD+ metabolome and 6 related nucleosides and nucleotides. Whereas yeast extract and nicotinic acid increase net NAD+ synthesis in a manner that can account for extended lifespan, glucose restriction does not alter NAD+ or nicotinamide levels in ways that would increase Sir2 activity.The results constrain the possible mechanisms by which calorie restriction may regulate Sir2 and suggest that provision of vitamins and calorie restriction extend lifespan by different mechanisms.The pyridine dinucleotide, NAD+, synthesized from the pyridine mononucleotides nicotinic acid mononucleotide (NaMN) or nicotinamide mononucleotide (NMN), is a unique cellular molecule that cycles between NAD+ and NADH co-enzymatically and is cleaved to produce nicotinamide (Nam) and acetylated ADPribose in protein lysine deacetylation by sirtuins [1]. Typically, eukaryotic de novo biosynthetic pathways produce NaMN from tryptophan through quinolinic acid (QA) and from the vitamin, nicotinic acid (NA). Eukaryotic salvage pathways produce NMN from Nam and/or nicotinamide riboside (NR) [2,3]. The biosynthetic pathways for NAD+ in Saccharomyces cerevisiae are schematized in Figure 1. Though most eukaryotic NAD+ biosynthetic pathways were described long ago, we have only recently determined the gene and enzyme basis for the NR kinase pathway [4], NR kinase-independent NR salvage [5,6], specific NR transport [7], specific utilization of nicotinic acid riboside (NAR) [8,9], and dephosphorylation of NMN and NaMN to NR and NAR [10].Several lines of reasoning indicate that the availability of salvageable vitamin precursors and the regulation of salvage enzymes are key determinants of Sir2 function. First, the NA salvage enzyme nicotinic acid phosphoribosyl transferase, Npt1, is required for the longevity benefit of calorie restriction (CR) [11]. Second,
|