X-Message-Number: 20444 Date: Thu, 14 Nov 2002 20:58:47 -0800 (PST) From: Doug Skrecky <> Subject: warning: accelerated aging by nicotinamide Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1 J Biol Chem September 23, 2002 (epub ahead of print) Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA Pathology, Harvard Medical School, Boston, MA 02115. The Saccharomyces cerevisiae Sir2 protein is an NAD+-dependant histone deacetylase that plays a critical role in transcriptional silencing, genome stability and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products: O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B3. We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recobination and leads to an eventual delocalization of Sir2 even in G1-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide non-competitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC50<50M) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD+, thereby blocking NAD+ hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regular of Sir2 enzymes. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=20444