Fig 8. Mechanism of deactylation of AHA by HDAC8.

In HDAC8 and other HDACs class I enzymes, the hydrogen bond forming between Tyr306 and the carbonyl oxygen of the acetyl moiety increases the electrophilicity of the carbonyl carbon, rendering it more susceptible to the nucleophilic attack by the activated water molecule, bound to His142 and His143. This leads to the formation of a tetrahedral oxyanion intermediate stabilized by Zn²⁺ ion and the hydroxyl group of Tyr306. Subsequently, the amide bond is cleaved and the acetyl moiety is released.