Superoxide dismutases (SODs) catalyze the disproportionation of superoxide to dioxygen and hydrogen peroxide. The active metal sites of iron and manganese superoxide dismutases are structurally indistinguishable from each other. Despite the structural homology, these enzymes exhibit a high degree of metal selective activity suggesting subtle redox tuning of the active site. The redox tuning model, however, up to now has been challenged by the existence of so-called cambialistic SODs that function with either metal ion. We have prepared and investigated two sets of manganese complexes in which groups of varying electron-withdrawing character, as measured by their Hammett constants σPara, have been introduced into the ligands. We observed that the Mn(III)/Mn(II) reduction potential for the series based on 4′-X-terpyridine ligands together with the corresponding values for the iron-substituted 4′-X-terpyridine complexes changed linearly with σPara. The redox potential of the iron and manganese complexes could be varied by as much as 600 mV by the 4′-substitution with the manganese complexes being slightly more sensitive to the substitution than iron. The difference was such that in the case where the 4′-substituent was a pyrrolidine group both the manganese and the iron complex were thermodynamically competent to catalytically disproportionate superoxide, making this particular ligand "cambialistic". Taking our data and those available from the literature together, it was found that in addition to the electron-withdrawing capacity of the 4′-substituents the overall charge of the Mn(II) complexes plays a major role in tuning the redox potential, about 600 mV per charge unit. The ion selectivity in Mn and FeSODs and the occurrence of cambialistic SODs are discussed in view of these results. We conclude that the more distant electrostatic contributions may be the source of metal specific enzymatic activity.
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