Copper-dependent inhibition of cytochrome c oxidase by Aβ 1-42 requires reduced methionine at residue 35 of the Aβ peptide

Abstract

By altering key amino acid residues of the Alzheimer's disease-associated amyloid-β peptide, we investigated the mechanism through which amyloid-β inhibits cytochrome c oxidase (EC 1.9.3.1). Native amyloid-β inhibited cytochrome oxidase by up to 65%, and the level of inhibition was determined by the period of amyloid-β ageing before the cytochrome oxidase assay. Substituting tyrosine-10 with alanine did not affect maximal enzyme inhibition, but the altered peptide required a longer period of ageing. By contrast, oxidizing the sulfur of methionine-35 to a sulfoxide, or substituting methionine-35 with valine, completely abrogated the peptide's inhibitory potential towards cytochrome oxidase. S..