Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes

Abstract

Metal-dependent histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins to yield L-lysine and acetate. This chemistry plays a critical role in the regulation of numerous biological processes. Aberrant HDAC activity is implicated in various diseases, and HDACs are validated targets for drug design. Two HDAC inhibitors are currently approved for cancer chemotherapy, and other inhibitors are in clinical trials. To date, X-ray crystal structures are available for four human HDACs (2, 4, 7, 8) and three HDAC-related deacetylases from bacteria (histone deacetylase-like protein, HDLP; histone deacetylase-like amidohydrolase, HDAH; acetylpolyamine amidohydrolase, APAH). Structural comparisons among these enzymes reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Structural analyses of HDACs and HDAC-related deacetylases guide the design of tight-binding inhibitors, and future prospects for developing isozyme-specific inhibitors are quite promising.

Mechanism of N-Acylthiourea-mediated Activation of Human Histone Deacetylase 8 (HDAC8) at Molecular and Cellular Levels

“…6), it implies that both the activator and the inhibitor (used to serve as a substrate analog) can simultaneously bind to the enzyme. This is not surprising in view of the marked malleability/flexibility of the active site pocket of HDAC8, as evident from its ability to interact with structurally diverse ligands with modest binding affinities (6,10,32,39). The kinetic (Fig.…”

“…3). The above structural/functional feature is further supported by the fact that the active site of HDAC8 is constituted by several pocket-forming loops, which are reportedly highly flexible in nature (6,10). Furthermore, since Trp-141 is a unique residue found only in the HDAC8 isozyme (10), it is not surprising that TM-2-51 serves as an isozyme-selective activator (22).…”

“…The benzoyl moiety of the activator at the second site makes a close contact with the indole moiety of Trp-141, which is located at the bottom end of the active site pocket of the enzyme (6). Hence, the activator bound at the second site has the potential to modulate the geometry of the catalytic pocket of the enzyme via a long-range allosteric interaction.…”

“…In humans, 18 different HDAC isozymes have been identified, and these are grouped, on the basis of their sequence homology to the gene/protein found in yeast, into four major classes (5). HDAC isozymes belonging to class I (HDAC1, -2, -3, and -8) and class II (HDAC4 -7, -9, and -10) require the Zn 2ϩ ion for their catalytic activities, and these enzymes are inhibited by canonical/"pan" inhibitors, such as trichostatin A, SAHA, and romidepsin, among others (1,2,5,6). Unlike the above two classes, class III HDACs (sirtuins) do not require the Zn 2ϩ ion for catalysis.…”

Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase Inhibition Activity of Hydroxamic Acid Derivatives

“…In case of SAHA and some other compounds, this H bond was instead donated by His145. According to the catalytic mechanism of HDAC inhibition, His145, His146, Asp181, His183, Asp269, and Tyr308 are responsible for the stabilization of the substrate in the binding site and form part of the charge relay system necessary for the zinc-dependent hydrolysis of the acetylated lysine substrates [49]. Moreover, hydrophobic interactions involved in holding ligands within the active site include interactions between the linker moieties and aromatic rings of Phe155 and Phe210.…”