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

► Histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-l-lysine. ► HDACs and related deacetylases adopt the α/β arginase fold. ► HDACs employ a promoted-water mechanism for catalysis. ► Potent HDAC inhibitors chelate the active site metal ion. ► Macrocyclic HDAC inhibitors interact with the mouth of the active site.