The stereoselectivity of alcohol dehydrogenases: a stereochemical imperative?

The stereoselectivity of NAD+-dependent alcohol dehydrogenases (transfering either the pro-R or pro-S hydrogen of NADH) correlates with the thermodynamic stability of their substrates, and appears to reflect evolutionary pressure to adjust in the active site the conformation of NADH so as to match the cofactor's reducing power to the oxidizability of the substrate. A requirement that the free energies of protein-bound intermediates be matched suggests a new approach for understanding catalysis and evolution in enzymes.