QM-cluster model study of CO2 hydration mechanisms in metal-substituted human carbonic anhydrase II

Human carbonic anhydrase (CA) metalloenzymes utilize a Zn2+-containing active site to catalyze the interconversion of carbon dioxide to bicarbonate. The Zn2+ ion may be replaced with other divalent transition metals, though the catalytic efficiency of the enzyme will be reduced. In this work, quantum mechanical cluster models of the active site are used to map the reaction profile for the hydration mechanism of carbon dioxide. The Lipscomb proton transfer and Lindskog rotation mechanisms were examined for the native Zn2+-enzyme along with variants where the metal was substituted with Cd2+, Ni2+, Fe2+, and Fe3+. The findings highlight the impact the metal coordination geometry has on the reaction profile. The results also suggest Fe2+, which is the functional metal for a prototypical CA of an anaerobic bacterium, might also be functional for human CA if cultured within an anaerobic environment.