Mutation of the Phe20 residue in Alzheimer's amyloid beta-peptide might decrease its toxicity due to disruption of the Met35-cupric site electron transfer pathway.
It has been proposed that the Met residue in the C-terminal domain of the Alzheimer's disease beta-amyloid peptide (betaA) serves as a source of electrons for the Cu(II)-catalyzed reduction of molecular oxygen to hydrogen peroxide. Mechanistically, this process would require the long distance electron transfer from the thioether sulfur to the peptide-bound copper. Therefore, the electron transfer pathways between the Met35 sulfur atom and the cupric site in the N terminus of betaA congeners have been analyzed applying semiclassical models of long distance electron transfer. Simulations performed for several betaA conformers collected along the 6 ns Langevin Dynamics trajectories suggest that the presence of the Phe20 residue in the peptide is required for feasibility of the electron transfer. Thus, I would like to propose the mutation Phe20Ala in betaA as a potential way to reduce its neurotoxicity.
Pogocki
Dariusz
D
Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland. pogo@orange.ichtj.waw.pl
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D003300:Copper / Q000378:metabolism*; D004579:Electron Transport; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000378:metabolism; D010649:Phenylalanine / Q000235:genetics*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010649:Phenylalanine; D003300:Copper; D008715:Methionine