THE FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS-ASSOCIATED AMINO-ACID SUBSTITUTIONS E1OOG, G93A, AND G93R DO NOT INFLUENCE THE RATE OF INACTIVATION OF COPPER-CONTAINING AND ZINC-CONTAINING SUPEROXIDE-DISMUTASE BY H2O2

Inactivation of copper-and zinc-containing superoxide dismutase (Cu,Zn SOD) by H2O2 is the consequence of several sequential reactions: reduc tion of the active site Cu(II) to Cu(I) by H2O2; oxidation of the Cu(I ) by a second H2O2, thus generating a powerful oxidant, which may be C u(I)O or Cu(II)OH or Cu(III); and finally oxidation of one of the hist idines in the ligand field, causing loss of SOD activity. Three famili al amyotrophic lateral sclerosis (FALS)-associated mutant Cu,ZnSODs, i .e., E100G, G93A, and G93R, did not differ from the control enzyme in susceptibility to inactivation by H2O2. It thus appears that an increa sed peroxidase activity of the FALS-associated Cu,ZnSOD variants might not be a factor in the development of this disease. This leaves the l oss of Zn, and the consequent increase in peroxidase activity, or in n itration activity, as a viable explanation (J. P. Crow et at, 1997, J. Neurochem. 69, 1936-1944), among other possibilities. (C) 1998 Academ ic Press.