Inhibitors of NAD+ Dependent Histone Deacetylases (Sirtuins)

Manfred      Jung; Robert   C.   Neugebauer; Wolfgang      Sippl

Abstract

Histone deacetylases (HDACs) are enzymes that deacetylate acetyl lysines in histones and various non-histone proteins. Three classes of histone deacetylases have been described in humans: class I, II and IV were shown to be zinc dependent amidohydrolases and eleven subtypes are known today (HDAC1-11). Class III enzymes depend in their catalysis on NAD+ with the subsequent formation of nicotinamide and O-acetyl-ADP ribose. Based on the homology to the yeast histone deacetylase Sir2p the NAD+-dependent deacetylases have been termed sirtuins and seven members (SIRT1-7) have been described in humans. Whereas class I and II HDACs have been identified as valid anticancer targets and clinical studies of their inhibitors as new anticancer agents are under way much less is known about the consequences of class III histone deacetylase inhibition. Sirtuins have been linked to ageing and overexpression of sirtuins leads to a prolonged lifespan in yeast. Lately, sirtuin activity has been tied to the pathogenesis of HIV, cancer and neurodegenerative disease. In the last two years several reports of new sirtuin inhibitors have emerged. Additionally, sirtuin activators have been identified and have been implicated as potential drugs for the ameloriation of metabolic diseases. Thus, the field of sirtuin biology can be investigated with these new tools which will allow in turn to assess the therapeutic potential of those compounds. We will present an overview over sirtuins and their available inhibitors and activators.

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