Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid

• Published in: Biochimica et biophysica acta Vol. 1792; no. 1; pp. 49 - 55
• Main Authors: da Silva, Giordano F.Z., Lykourinou, Vasiliky, Angerhofer, Alexander, Ming, Li-June
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 2009
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Ascorbic acid; Binding Sites; Catechol oxidase; Catechol Oxidase - chemistry; Catechol Oxidase - metabolism; Copper; Copper - chemistry; Dopamine - metabolism; Electron Spin Resonance Spectroscopy; Humans; In Vitro Techniques; Kinetics; Methionine; Methionine - chemistry; Models, Chemical; Oxidation-Reduction; Oxidative Stress; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Reducing agent; Reducing Agents; β-amyloid; APP; AD; Ascorbic acid; EPR; NQI; Methionine; Catechol oxidase; ESEEM; Reducing agent; MBTH; Aβ; NMR; HEPES; ROS; Copper; GSH; Alzheimer's disease; β-amyloid
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2008.11.004

The potential risk of metal-centered oxidative catalysis has been overlooked in the research of the copper complexes of the Alzheimer's disease-related β-amyloid (Aβ) peptides. Cu 2+ complexes of Aβ 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 2O 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–β-amyloid and neuropathology of Alzheimer's disease, Angew. Chem. Int. Ed. 46 (2007) 3337–3341]. The results further support the metallo-Aβ-associated oxidative stress theory often considered to be connected to the neuropathology of the disease. The metal-centered oxidative catalysis of CuAβ 1–16/20 challenges the long-standing proposed redox role of Met35 in Aβ because Aβ 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 CuAβ 1–40 and CuAβ 1–20 with K d = 2.8 mM and 11.3 μM, respectively, which reflects less accessibility of the metal center in the full-length CuAβ 1–40. However, Met does not serve as a reducing agent for the Cu(II) which thus must amplify the observed oxidative catalysis of CuAβ 1–20 through a non-redox mechanism. Conversely, the CuAβ-catalyzed oxidation reaction of dopamine is inhibited by bio-available reducing agents such as ascorbate (competitive K ic = 66 μM) and glutathione (non-competitive, K inc = 53 μM). These data indicate that the oxidation chemistry of metallo-Aβ is not initiated by Met35. The results yield further molecular and mechanistic insights into the roles of metallo-Aβ in this disease.