Mutations in copper-zinc superoxide dismutase (CuZn-SOD) have been implicated in the familial form of the motor neuron disease amyotrophic lateral sclerosis (Lou Gehrig's disease). We have expressed and purified recombinant human wild type (hWT) and G93A (hG93A) CuZn-SOD, and we have used pulse radiolysis to measure their superoxide dismutase activities and their rates of deactivation upon exposure to hydrogen peroxide or heat. Both hG93A and hWT CuZn-SOD were found to have high SOD activities in their copper and zinc containing as-isolated forms as well as when remetallated entirely with copper (CuCu). Rates of deactivation by hydrogen peroxide of the as-isolated hWT and hG93A enzymes were determined and were found to be similar, suggesting that the FALS mutant enzyme is not inactivated at a higher rate than wild type by generation of and subsequent reaction with hydroxyl radical, .OH, when it is in the CuZn form. However, rates of deactivation by hydrogen peroxide of the CuCu derivatives of both hWT and hG93A were significantly greater than those of the copper and zinc containing as-isolated enzymes. Rates of thermal deactivation were also similar for the mutant and hWT as-isolated CuZn forms but were greater for the CuCu derivatives of both enzymes. Reactions of hydrogen peroxide with the Cu(II)Cu(II) derivative of the WT enzyme demonstrate that the copper ion in the copper site is reduced much more rapidly than the copper in the zinc site, leading to the conclusion that reaction of hydrogen peroxide with Cu(I) in the copper site is the source of deactivation in the CuCu as well as the CuZn enzymes.