Regulations of Sirtuins by NAD+ Biosynthesis in Saccharomyces cerevisiae

Sirtuins are an evolutionarily conserved family of NAD + -dependent protein deacetylases, which have been shown to play important roles in the regulation of gene transcription, cellular metabolism, and aging. Optimal sirtuin activity requires the maintenance of adequate intracellular NAD + concentration through the combined action of NAD + biosynthesis and salvage pathways. Nicotinamide (NAM) is a key NAD + precursor that is generated as a byproduct of the sirtuin-mediated deacetylation reaction, but also inhibits the enzyme. Isonicotinamide (INAM) is an isostere of NAM that has been shown to activate yeast Sir2 by antagonizing the inhibition caused by NAM, leads to enhanced transcriptional silencing. We have now determined that INAM also activates Sir2 through an additional mechanism in vivo, which is by inducing an increase of the intracellular NAD + concentration. Nicotinamide riboside (NR) is a newly discovered NAD + precursor that can be utilized by two independent pathways for NAD + biosynthesis. Both NR and INAM can restore the NAD + concentration in vitamindepleted media and extend replicative lifespan. Additionally the addition of INAM can stimulate the related yeast sirtuin, Hst1, to modify the epigenetic properties of rDNA silencing such that the silenced state became measurably heritable, a phenotype not previously ascribed to the yeast rDNA.

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