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J. Biol. Chem., Vol. 280, Issue 17, 16601-16609, April 29, 2005

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Catechol Oxidase-like Oxidation Chemistry of the 1–20 and 1–16 Fragments of Alzheimer's Disease-related -Amyloid Peptide

THEIR STRUCTURE-ACTIVITY CORRELATION AND THE FATE OF HYDROGEN PEROXIDE^*

Giordano F. Z. da Silva, William M. Tay, and Li-June Ming

From the Department of Chemistry and Institute for Biomolecular Science, University of South Florida, Tampa, Florida 33620-5250

The Cu²⁺ complexes of the 1–16 and the 1–20 fragments of the Alzheimer's disease-related -amyloid peptide (CuA) 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 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) and k_cat/K_m of 37.2 M^–1s^–1 under saturating [H₂O₂] of 0.24%. This kinetic profile is consistent with metal-centered redox chemistry for the action of CuA. 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 aerobically without H₂O₂, affording rate constants of 6.50 x 10^–3 s^–1 and 3.25 M^–1s^–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 O₂ binding to afford the µ-²:²-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, hyperfine-shifted ¹H NMR spectrum of CoA, and molecular mechanics calculations. The results presented here are expected to add further insight into the chemistry of metallo-A, which may assist better understanding of the neuropathology of Alzheimer's disease.

Received for publication, October 12, 2004 , and in revised form, February 3, 2005.

^* This work on metallopeptides structure and activity was supported by the Research and Creative Award of the University of South Florida and the Petroleum Research Fund administrated by the American Chemical Society (Grant PRF AC 40851-AC3). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

L.-J. M. dedicates this article to his mother and to Dr. Shwu-Yeng Lin, who with great patience and kindness have been caring for their beloved better halves through some very difficult times of "losing mind." G. F. Z. S. dedicates this article to Ayres Baptista Mello and family, whose struggle with Alzheimer's disease has fueled the author's desire in gaining a better understanding of the mechanisms of this disease at the molecular level.

To whom correspondence should be addressed: Dept. of Chemistry and Institute for Biomolecular Science, University of South Florida, 4202 E. Fowler Ave., SCA400, Tampa, FL 33620-5250. Tel.: 813-974-2220; Fax: 813-974-3203; E-mail: ming{at}shell.cas.usf.edu.

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