Figure 2.

Summary of the HDAC8 mechanism. Coordination to Zn²⁺ and hydrogen bonding with Y306 activates the scissile carbonyl of acetyllysine for nucleophilic attack by a Zn²⁺-bound water molecule with the assistance of general base H143. Electrostatic stabilization of the resulting tetrahedral intermediate is achieved by Zn²⁺ and H142. Proton donation to the leaving amino group by H143 enables collapse of the tetrahedral intermediate to form free lysine and acetate.