Methionine does not reduce Cu(II)-beta-amyloid!--rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)-beta-amyloid.
The potential risk of metal-centered oxidative catalysis has been overlooked in the research of the copper complexes of the Alzheimer's disease-related beta-amyloid (Abeta) peptides. Cu(2+) complexes of Abeta(1-40) and its 1-16 and 1-20 fragments have recently been shown to exhibit significant metal-centered oxidative activities toward several catecholamine neurotransmitters with and without H(2)O(2) around neutral pH [G.F.Z. da Silva, L.-J. Ming, "Metallo-ROS" in Alzheimer's disease: metal-centered oxidation of neurotransmitters by Cu(II)-beta-amyloid and neuropathology of Alzheimer's disease, Angew. Chem. Int. Ed. 46 (2007) 3337-3341]. The results further support the metallo-Abeta-associated oxidative stress theory often considered to be connected to the neuropathology of the disease. The metal-centered oxidative catalysis of CuAbeta(1-16/20) challenges the long-standing proposed redox role of Met35 in Abeta because Abeta(1-16/20) do not contain a Met. External Met has been determined by kinetic, optical, and electron paramagnetic resonance methods to bind directly to the Cu(2+) center of CuAbeta(1-40) and CuAbeta(1-20) with K(d)=2.8 mM and 11.3 microM, respectively, which reflects less accessibility of the metal center in the full-length CuAbeta(1-40). However, Met does not serve as a reducing agent for the Cu(II) which thus must amplify the observed oxidative catalysis of CuAbeta(1-20)through a non-redox mechanism. Conversely, the CuAbeta-catalyzed oxidation reaction of dopamine is inhibited by bio-available reducing agents such as ascorbate (competitive K(ic)=66 microM) and glutathione (non-competitive, K(inc)=53 microM). These data indicate that the oxidation chemistry of metallo-Abeta is not initiated by Met35. The results yield further molecular and mechanistic insights into the roles of metallo-Abeta in this disease.
da Silva
Giordano F Z
GF
Department of Chemistry and Institute for Biomolecular Science, University of South Florida, Tampa, FL 33620-5250, USA.
Lykourinou
Vasiliky
V
Angerhofer
Alexander
A
Ming
Li-June
LJ
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004156:Catechol Oxidase / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D004298:Dopamine / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008715:Methionine / Q000737:chemistry*; D008956:Models, Chemical; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D019163:Reducing Agents
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019163:Reducing Agents; C433241:amyloid beta-protein (1-16); C078592:amyloid beta-protein (1-40); D003300:Copper; D008715:Methionine; D004156:Catechol Oxidase; D004298:Dopamine