Identification and Characterization of Sir2 Inhibitors Through Phenotypic Assays in Yeast

Author(s): Jeff Posakony, Maki Hirao, Antonio Bedalov

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 7 , Issue 7 , 2004

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Abstract:

Yeast Sir2 is a defining member of a large family of protein deacetylases found in organisms ranging from bacteria to humans. SIR2 was discovered as a gene required for mating in S. cerevisiae 25 years ago, but it was only recently that Sir2s activity as an NAD-dependent protein deacetylase was established. However, years of extensive research did generate a large body of knowledge about the cellular roles of Sir2 in yeast long before its biochemical function was discovered. In addition to Sir2, yeast have four additional NAD-dependent histone deacetylases Hst1-4 (for homologue of Sir2), with distinct cellular roles. Detailed knowledge of the phenotypes of SIR2 and HST loss of function mutants has allowed design of a series of cell based screens that yielded the first inhibitors of NAD-dependent protein deacetylases. These phenotypic assays, amenable to high throughput screening, and coupled with transcript array analysis for evaluation of compound specificity, allowed the identification and detailed characterization of a series of Sir2 inhibitors, entirely bypassing traditional biochemical approaches.XXXY YYZZZ

Keywords: deacetylase inhibitors, sir2 inhibitors, yeast-based phenotypic assays, splitomicin

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Article Details

VOLUME: 7
ISSUE: 7
Year: 2004
Page: [661 - 668]
Pages: 8
DOI: 10.2174/1386207043328346
Price: $65

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