Comprehensive reaction mechanisms at and near the Ni-Fe active sites of [NiFe] hydrogenases

[NiFe] hydrogenase (H(2)ase) catalyzes the oxidation of dihydrogen to two protons and two electrons and/or its reverse reaction. For this simple reaction, the enzyme has developed a sophisticated but intricate mechanism with heterolytic cleavage of dihydrogen (or a combination of a hydride and a proton), where its Ni-Fe active site exhibits various redox states. Recently, thermodynamic parameters of the acid-base equilibrium for activation-inactivation, a new intermediate in the catalytic reaction, and new crystal structures of [NiFe] H(2)ases have been reported, providing significant insights into the activation-inactivation and catalytic reaction mechanisms of [NiFe] H(2)ases. This Perspective provides an overview of the reaction mechanisms of [NiFe] H(2)ases based on these new findings.