Catechol oxidase-like oxidation chemistry of the 1-20 and 1-16 fragments of Alzheimer's disease-related β-amyloid peptide -: Their structure-activity correlation and the fate of hydrogen peroxide

The Cu2+ complexes of the 1 - 16 and the 1 - 20 fragments of the Alzheimer's disease-related beta-amyloid peptide (CuA beta) show significant oxidative activities toward a catechol-like substrate trihydroxylbenzene and plasmid DNA cleavage. The latter reflects possible oxidative stress to biological macromolecules, yielding supporting data to the pathological role of these soluble A beta fragments. The former exhibits enzyme-like kinetics and is dependent on [H2O2], exhibiting k(cat) of 0.066 s(-1) (6000-fold higher than the reaction without CuA beta) and k(cat)/K-m of 37.2 M-1 s(-1) under saturating [H2O2] of similar to 0.24%. This kinetic profile is consistent with metal-centered redox chemistry for the action of CuA beta. A mechanism is proposed by the use of the catalytic cycle of dinuclear catechol oxidase as a working model. Trihydroxylbenzene is also oxidized by CuA beta aerobically without H2O2, affording rate constants of 6.50 x 10(-3) s(-1) and 3.25 M-1 s(-1). This activity is also consistent with catechol oxidase action in the absence of H2O2, wherein the substrate binds and reduces the Cu2+ center first, followed by O-2 binding to afford the mu-eta(2): eta(2)-peroxo intermediate, which oxidizes a second substrate to complete the catalytic cycle. A tetragonally distorted octahedral metal coordination sphere with three coordinated His side chains and some specific H-bonding interactions is concluded from the electronic spectrum of CuA beta, hyperfine-shifted H-1 NMR spectrum of CoA beta, and molecular mechanics calculations. The results presented here are expected to add further insight into the chemistry of metallo-A beta, which may assist better understanding of the neuropathology of Alzheimer's disease.