We propose that the apparent catalytic inactivity of Mn- and Fe-substituted superoxide dismutases (SODs) reflects E degrees s that are either lower (Fe-sub-(Mn)SOD) or higher (Mn-sub-(Fe)SOD) than those of native Fe- or Mn-SODs. In support, we show that the E degrees of Fe-sub-(Mn)SOD (Fe substituted into Mn-SOD protein) is -240 mV vs NHE, almost 0.5 V lower than our E degrees of 220 mV for Fe-SOD. The E degrees of Fe-sub-(Mn)SOD is lower than that of O-2/O-2(.-) and therefore is sufficient to explain Fe-sub-(Mn)SOD's inactivity. Indeed, Fe-sub-(Mn)SOD is shown to be unable to oxidize O-2(.-). Alternate causes of inactivity are ruled out by our demonstration that Fe-sub-(Mn)SOD retains the ability to reduce O-2(.-). Thus, the active site remains active with respect to substrate binding and proton and electron transfer. Finally, we show that Fe-sub-(Mn)SOD's inactivity with respect to O-2(.-) oxidation cannot be solely due to competitive inhibition by OH-. Thus, our proposal provides a simple chemical basis for the observed catalytic inactivity of metal-exchanged Mn- or Fe-SODs and suggests that these strongly homologous enzymes may provide important insights into mechanisms of redox midpoint potential tuning in proteins.