Scheme 3.

Proposed mechanisms for alcohol dehydrogenases featuring inverse solvent isotope effects associated with rapid equilibria. (a) Ligand displacement of a Zn²⁺-bound water by the substrate gives rise to an inverse SEIE in the yeast alcohol dehydrogenase (YADH)-catalyzed reduction of p-methoxybenzaldehyde. (b) Transfer of a hydron from a Zn²⁺-bound water to the alkoxide intermediate yields an inverse SEIE in the liver alcohol dehydrogenase (LADH)-catalyzed reduction of 4-(2′-imidazolyl)azobenzaldehyde by NADD.