Oxidative Stress and the CNS

Yim

Dr. Grover: �We appreciate your concern about the high Km values for H2O2. �At a low concentration of H2O2 (submillimolar range), we can also clearly detect hydroxyl radicals. �The difference in the adduct concentration generated by the mutants and wild-type is larger at the lower concentration. �Although the concentration of peroxide cannot reach the Km value in vivo, the damaged species are produced and accumulate with time. �Also, the free radical reaction is a chain reaction: one of its characteristics is that the small difference in initial hydroxyl radical concentration amplifies itself through chain carriers (secondary radicals) to generate a larger difference in the amount of damaged products. �The k(cat) values of both mutants are identical to that of wild-type enzyme (ref. 9, 10). �Thus the differential in free radical generation, higher with mutant enzymes, is derived from the difference in Km values. This is consistent with free radicals playing a critical role in the progression of FALS, which is an age-dependent disorder. �Its onset occurs at the age of about 45-50 years when the protective system against oxidative stress becomes sufficiently weak. �Allow me to speculate that low Km values for H2O2 in free radical-generating activity would be detrimental to living systems.