Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening

Christina M. Grozinger, Elizabeth D. Chao, Helen E. Blackwell, Danesh Moazed, Stuart L. Schreiber

Research output: Contribution to journalArticle

429 Citations (Scopus)

Abstract

The yeast transcriptional repressor Sir2p silences gene expression from the telomeric, rDNA, and silent mating-type loci and may play a role in higher order processes such as aging. Sir2p is the founding member of a large family of NAD-dependent deacetylase enzymes, named the sirtuins. These proteins are conserved from prokaryotes to eukaryotes, but most remain uncharacterized, including all seven human sirtuins. A reverse chemical genetic approach would be useful in identifying the biological function of sirtuins in a wide variety of experimental systems, but no cell-permeable small molecule inhibitors of sirtuins have been reported previously. Herein we describe a high throughput, phenotypic screen in cells that led to the discovery of a class of sirtuin inhibitors. All three compounds inhibited yeast Sir2p transcriptional silencing activity in vivo, and yeast Sir2p and human SIRT2 deacetylase activity in vitro. Such specific results demonstrate the utility and robustness of this screening methodology. Structure-activity relationship analysis of the compounds identified a key hydroxy-napthaldehyde moiety that is necessary and sufficient for inhibitory activity. Preliminary studies using one of these compounds suggest that inhibition of sirtuins interferes with body axis formation in Arabidopsis.

Original languageEnglish (US)
Pages (from-to)38837-38843
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number42
DOIs
StatePublished - Oct 19 2001

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Sirtuins
NAD
Screening
Molecules
Yeast
Yeasts
Reverse Genetics
Structure-Activity Relationship
Ribosomal DNA
Eukaryota
Arabidopsis
Gene expression
Aging of materials
Throughput
Gene Expression
Enzymes
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Grozinger, Christina M. ; Chao, Elizabeth D. ; Blackwell, Helen E. ; Moazed, Danesh ; Schreiber, Stuart L. / Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 42. pp. 38837-38843.
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Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening. / Grozinger, Christina M.; Chao, Elizabeth D.; Blackwell, Helen E.; Moazed, Danesh; Schreiber, Stuart L.

In: Journal of Biological Chemistry, Vol. 276, No. 42, 19.10.2001, p. 38837-38843.

Research output: Contribution to journalArticle

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