Histone deacetylases (HDACs) constitute an important family of zinc-dependent enzymes responsible for catalyzing the cleavage of acetyl groups from acetyl-lysine residues in histone N-terminal tails. HDACs can potentially play a key role treating various cancer, thus making knowledge of their catalytic mechanism highly important. Based on exptl. structures, the initially proposed mechanism hypothesized enhancement of active water nucleophilicity by coordination to the zinc atom. Our theor. study does not support the previous hypothesis but suggests a new catalytic mechanism for this important reaction. [on SciFinder (R)]