A catalytically active [Mn]-hydrogenase incorporating a non-native metal cofactor

Nature carefully selects specific metal ions for incorporation into the enzymes that catalyze the chemical reactions necessary for life. Hydrogenases, enzymes that activate molecular H(2), exclusively utilize Ni and Fe in [NiFe]-, [FeFe]-, and [Fe]-hydrogeanses. However, other transition metals are known to activate or catalyze the production of hydrogen in synthetic systems. Here, we report the development of a biomimetic model complex of [Fe]-hydrogenase that incorporates a Mn, as opposed to a Fe, metal center. This Mn complex is able to heterolytically cleave H(2) as well as catalyze hydrogenation reactions. Incorporation of the model into an apoenzyme of [Fe]-hydrogenase results in a [Mn]-hydrogenase with enhanced occupancy-normalized activity over an analogous semi-synthetic [Fe]-hydrogenase. These findings represent the first instance of a non-native metal hydrogenase showing catalytic functionality and demonstrate that hydrogenases based on a manganese active site are viable.