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Copper‐dependent inhibition of cytochrome c oxidase by Aβ 1−42 requires reduced methionine at residue 35 of the Aβ peptide
Author(s) -
Crouch Peter J.,
Barnham Kevin J.,
Duce James A.,
Blake Rachel E.,
Masters Colin L.,
Trounce Ian A.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04050.x
Subject(s) - cytochrome c oxidase , chemistry , biochemistry , cytochrome , peptide , oxidase test , cytochrome c , sodium dodecyl sulfate , enzyme , mitochondrion
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. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis analysis revealed that the loss of inhibitory potential towards cytochrome oxidase with the methionine‐35‐altered peptides did not correlate with a substantially different distribution of amyloid‐β oligomeric species. Although the amyloid‐β‐mediated inhibition of cytochrome oxidase was completely dependent on the presence of divalent Cu 2+ , it was not supported by monovalent Cu + , and experiments with catalase and H 2 O 2 indicated that the mechanism of cytochrome oxidase inhibition does not involve amyloid‐β‐mediated H 2 O 2 production. We propose that amyloid‐β‐mediated inhibition of cytochrome oxidase is dependent on the peptide's capacity to bind, then reduce Cu 2+ , and that it may involve the formation of a redox active amyloid‐β‐methionine radical.