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.

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