ABSTRACT
Protein acetylation is involved in the regulation of several cellular functions such as protein-protein interactions, protein stability, and DNA recognition by proteins. For instance, the acetylation of histone proteins alters gene transcription [1]. Thus, removal of acetyl groups from lysine residues results in compaction of chromatin and, hence, repression of gene transcription. The process of acetylation and deacetylation regulated by proteins with acetyltransferase activity is important for cellular processes. These proteins are usually known as histone acetyltransferases [2]. Nowadays, there is a growing interest for histone deacetylases (HDACs) because of their potential clinical applications [3]. HDACs have been divided into four groups. Class I and class II HDACs are similar to the yeast Rpd3p and Hda1p proteins. Class III HDACs are similar to the yeast transcriptional repressor Sir2p and are referred to as sirtuins. Class I and class II HDACs are characterized by
22.1 Introduction ........................................................................................................................ 329 22.2 SIRT1 and Neuroprotection ................................................................................................ 331 22.3 Resveratrol .......................................................................................................................... 331 22.4 Resveratrol and Huntington’s Disease ................................................................................ 333 22.5 Resveratrol and Alzheimer’s Disease ................................................................................. 334 22.6 Resveratrol and Parkinson’s Disease .................................................................................. 334 22.7 Resveratrol in Stroke and Brain Damage ........................................................................... 335 22.8 Resveratrol and Aging ........................................................................................................ 335 22.9 Hormesis: Axis between SIRT1 and Resveratrol? .............................................................. 336 22.10 Summary ............................................................................................................................ 336 Acknowledgments .......................................................................................................................... 337 References ...................................................................................................................................... 337
their sensitivity to inhibition by trichostatin A, while class III HDACs are dependent on nicotinamide adenine dinucleotide (NAD). Class IV HDACs include the deacetylase HDACII. The focus of this chapter is on sirtuins (class III HDAC), which are a conserved family of NAD+-dependent deacetylases and named after the founding member, Saccharomyces cerevisiae silent information regulator 2 (Sir2) protein [4]. Its products function in a complex as transcriptional repressors or silencers, acting largely through histone deacetylation, at the telomeres, mating-type loci, and the rDNA gene loci [5] . The SIR2 gene, required for silencing of rDNA loci, is evolutionarily conserved from prokaryotes to humans. Sir2 is a NAD-dependent class III protein deacetylase [6,7], with ADP-ribosyltransferase activity in vitro. Analysis of SIRT1 enzymatic activity has revealed that it functions differently from previously described HDACs. Studies using puried SIRT1 revealed that for every acetyl lysine group removed, one molecule of NAD is cleaved, and nicotinamide and O-acetyl-ADP-ribose are produced (Figure 22.1). Therefore, SIRT1 appears to possess two enzymatic activities: the deacetylation of a target protein and the metabolism of NAD [8,9]. These two activities suggest that SIRT1 could act as a metabolic or oxidative sensor, regulating cellular machinery based on such information.
