Histone deacetylase

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

Repression of genes is associated with reversal of this process under the control of histone deacetylases (HDACs). Deacetylation of histones increases the winding of DNA round histone residues, resulting in a dense chromatin structure and reduced access of transcription factors to their binding sites, thereby leading to repressed transcription of inflammatory genes. 

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

Histone Deacetylases (HDACs) catalyze the removal of the acetyl groups from lysines (see Fig. 1). Together with the HATs they are responsible for maintaining the level of histone acetylation throughout the genome. The family of HDAC proteins has been divided into four classes based on phylogenetic analysis and sequence comparison. HDACs of the classes I and II share the same Zn2+-based reaction and are evolutionary related. Class IV HDACs also possess a Zn2+-based reaction... 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

Histone Acetylation Histone Deacetylases Histone Methylation Histone Phosphorylation Histone Tails Hrv... 

Fischle W, EmUiani S, Hendzel Ml, Nagase T, Nomura N, Voelter W, Verdin E (1999) A new family of human histone deacetylases related to Saccharomyces cerevisiae HDAlp. J Biol Chem 274(17) 11713-11720... 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

Corminboeuf C, Hu P, Tuckerman ME, Zhang Y (2006) Unexpected catalytic mechanism for histone deacetylase suggested by a density functional theory QM/MM study. J Am Chem Soc 128 4530 1531... 

Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family functional implications of phylogenetic analysis. J Mol Biol 338 17-31... 

Acharya MR, Sparreboom A, Venitz J, Figg WD (2005) Rational development of histone deacetylase inhibitors as anticancer agents a review. Mol Pharmacol 68 917-932... 

Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005) Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45 495-528... 

Kelly WK, Marks PA (2005) Drug insight histone deacetylase inhibitors - development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2 150-157... 

Marks PA, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer causes and therapies. Nat Rev Cancer 1 194-202... 

Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the tsa and saha inhibitors. Nature 401 188-193... 

Kapustin GV, Fejer G, Gronlund JL, Mccafferty DG, Seto E, Etzkorn FA (2003) Phosphorus-based saha analogues as histone deacetylase inhibitors. Org Lett 5 3053-3056... 

A series of aryltriazolylhydroxamates were reported as histone deacetylase (HDAC) inhibitors, exemplified by 49 (HDAC IC50 = 9.6 nM) which exhibited activity (L.d. IC50 = 4.5 pg/ mL) in an in vitro antileishmanial assay [48]. 

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