The reversible acetylation of histones plays a critical proteins and small molecules is critical for many other cellular processes. There is increasing evidence that the role in transcriptional regulation in eukaryotic cells, and there is mounting evidence that acetylation of non-his- function of several other proteins is also regulated by their acetylation state. For example, the DNA binding tone substrates is important for other cellular processes (reviewed in [1]). Two families of deacetylase enzymes activity of p53, E2F1, EKLF, and GATA1 is enhanced by the acetylation of a lysine residue, and acetylation of have been identified: the histone deacetylases, or HDACs, and the Sir2 (silent information regulator)-like α-tubulin appears to stabilize microtubules. Thus, acetylation of lysine residues and the negation of the positive family of NAD-dependent deacetylases, or sirtuins (reviewed in [2]). Both families have been evolutionarily charges associated with these side chains may be a general mechanism for altering protein structures or conserved from prokaryotes to humans, and both consist of several different proteins with nonredundant cel- protein-protein interactions, much like phosphorylation (reviewed in 1). In addition to proteins, small organic lular functions, many of which involve transcriptional regulation. Several processes have evolved to control molecules in the cell are also dynamically acetylated and deacetylated. Notably, polyamines such as spermidine the activity of deacetylases; such processes range from the recruitment of these proteins by specific transcrip- and spermine appear to function in DNA condensation processesasfreeaminesandareinactivatedbyacetylation factors to the more general inactivation of the deacetylases by sequestration. In the case of HDACs, tion of these amine groups [5]. Hence, while it is clear that histone acetyltransferases and histone deacetysmall-molecule inhibitors have proven to be crucial for the identification and subsequent characterization of lases are critical for the regulation of transcription, these proteins, or unidentified proteins, undoubtedly function these enzymes. Structural differences among the members of this family suggest that it will be possible to in other cellular processes as well. develop specific inhibitors for each of these proteins, which would be useful for elucidating their individual The HDAC and Sirtuin Families of Deacetylases cellular functions. In the case of the sirtuins, no func-There have been two families of deacetylases identified tional characterization of any of the human proteins has in eukaryotes, the histone deacetylases, or HDACs, and been reported. Thus, the recent identification of a sirtuin the Sir2-like deacetylases, or sirtuins. The HDAC endeacetylase inhibitor [3] may provide a very powerful zymes possess a highly conserved catalytic domain of tool for studying the biology of these enzymes. approximately 390 amino acids and appear to deacetylate their substrates by activating a water molecule with