Histone deacetylase-like protein

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. 

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

Wang, D.E., Wiest, O., Helquist, P., Lan-Hargest, H.Y andWiech, N.L. (2004) On the function of the 14 A long internal cavity of histone deacetylase-like protein implications for the design of histone deacetylase inhibitors. Journal of Medicinal Chemistry, 47, 3409-3417. 

Fig. 12-3 The X-ray structure of a bacterial corresponds to that of Fig. 12-4. with the histone deacetylase-like protein catalytic zinc in purple. Source T. A. Miller,...

C3P 1.8 0.198 A. aeolicus histone deacetylase-like protein rec... 

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. 

Enzymes that cleave off modifications may be assayed by measuring the formation of either the protein or a protein-mimicking substrate or the small molecule produd or byproducts (like acetate for histone deacetylases, or formaldehyde or hydrogen peroxide for histone demethylases). Transferases may generally be screened by measuring the conversion of the cosubstrate or quantitatin the formation of the... 

Several targets like kDNA replication machinery, purine salvage pathway, purine and pyrimidine biosynthetic pathway, histone deacetylase, DNA topoisomerases, membrane transporter proteins, glycoproteins and glycolipids are discussed in this book. 

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