Eukaryotic HDACs

Acetylation of internal lysine residues of core histone N-terminal domains has been found correlatively associated with gene transcription in eukaryotes for more than four decades. Histone acetylation levels are the result of a competition between two families of enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs). 

The correlation between histone acetylation and eukaryotic transcription were recognized many years ago [128,129]. However, it has not been until very recently, with the discovery that both HATs [130-133] and HDACs [134-138] are an integral part of the basal transcriptional machinery, that the molecular link for this correlation was established. This discovery has rekindled interest in this post-translational histone modification with implications ranging from basic chromatin research to applied medical investigations. Indeed, histone acetylation has been linked to cancer [139-144] and certain types of HDAC inhibitors are already being used to treat certain forms of cancer [145]. 

R., Gallinari, P. et al. (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDACS, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 101 (42), 15064-15069. 

Compared to the zinc-dependent HDACs, the sirtuins act by a very different mechanism and require NAD+ as a cofactor. Unsurprisingly, they show no sequence similarity with the other HDACs and are structurally very distinct [97]. The size of most sirtuins (Sirt2 to Sirt7) varies from 310 to 400 amino acid residues, while Sirtl is larger (747 residues). Multiple crystal structures of eukaryotic and prokaryotic sirtuin proteins have been reported, which either are apo-forms or include ligands such as NAD+ derivatives, W-acetylated lysine substrates, and/or other small molecules [98-110]. These data have shed much light on the mode of action of this enzyme class. 

A dedicated effort to clone additional HDACs from eukaryotic genomes revealed at least eight distinct genes—it is very likely that more will be identified once the emerging sequences of metazoan genomes, nematode, insect, rho-dent, and primate, are analyzed in sufficient detail. Several general observations can be made at this time, however. From a functional standpoint, many of the HDACs have been functionally connected to transcriptional repression pathways two examples are informative. 

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