Second-Sphere Tuning of the Metal Ion Reduction Potentials in Iron and Manganese Superoxide Dismutases

Iron and manganese superoxide dismutases (Fe- and MnSODs, respectively) are metalloenzymes that catalyze the disproportionation of superoxide to dioxygen and hydrogen peroxide whereby the metal ion cycles between an oxidized and one-electron reduced state. Although Fe- and MnSODs exhibit similar protein and active-site structures, they display strict metal-ion specificities. To understand the origin of this specificity, we performed spectroscopic and computational studies of various FeSOD species and found that certain second-sphere residues exert significant control over the proton-coupled metal ion reduction potential, which must be tuned differently for active site-bound Fe and Mn to permit both substrate oxidation and reduction.