Superoxide-Dependent Peroxidase Activity of H48Q: A Superoxide Dismutase Variant Associated with Familial Amyotrophic Lateral Sclerosis

Approximately 20% of cases of familial amyotrophic lateral sclerosis are caused by dominant mutations in the Cu,Zn superoxide dismutase. One such mutant, in which histidine #48 has been replaced by glutamine (H48Q), exhibits a novel activity. It can react sequentially with O−2and H2O2to generate a potent oxidant at its active site, possibly Cu(II)–OH, which then can oxidize urate to the corresponding radical. This O−2-dependent peroxidase activity exerted on a substrate peculiar to motor neurons may be the toxic gain of function which leads to the deleterious consequences of this mutation. G93A, G93R, and E100G were also examined and found not to exert this O−2-dependent peroxidase activity.