Structural Aspects of Zinc-Dependent Histone Deacetylases

2 Structural Aspects of Zinc-Dependent Histone Deacetylases 

The key to understanding the function of histone deacetylases lies in their three dimensional architecture. As outlined above, the class I, II, and IV enzymes are all metal ion dependent in most cases, a zinc ion is essential for activation and hydrolysis of the amide group, which is located within the active site of the enzyme. However, it has been shown that other metal ions can efficiently adopt the role of the catalytic ion. For instance, the nature of the ion bound to the catalytic site influences the specific activity of HDAC8 in the following order Co2+ Fe2+ Zn2+ Ni2+. These data suggest that Fe2+ rather than Zn2+ may be responsible for the in vivo activity of HDAC8 [33]. 

Several crystal structures of different HD AC subtypes and HD AC-like proteins have been published over the past decade. Related to the zinc-dependent enzymes, structural information is available for the class I enzymes HDAC2 [34] and HDAC8 [35, 36]. The recent HDAC2 structure revealed a foot pocket in proximity of the zinc ion, which can be accessed by small molecules [34]. This pocket contains multiple water molecules, which can be replaced by an inhibitor. 

This section is intended to give an overview of the known structural chemotypes of Zn2+-dependent Ve-acetyl lysine deactylase inhibitors and will not be restricted to compounds with known brain-permeability and/or potential as a therapeutic agent for a neurodegenerative disease. Molecules with known activity related to neurodegenerative diseases will be discussed in the context of the specific neurological disorders further below. Complementary to this review, Wang and Dymock have recently published an extensive survey of the recent patent literature covering histone deacetylase inhibitors [47]. 

The hydroxamic acid-based HDAC inhibitors can be further divided according to the nature of their linker and surface recognition elements. It is apparent from the literature that the linker region may be conformationally flexible and linear (e.g., Zolinza) or conformationally rigid as exemplified by the olefin TSA (2) and the cinnamide-type pyrrole 3 [51] shown below. Compounds in which the hydroxamate war head is directly attached to an aryl or heteroaryl group have been investigated as well. 

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