PNNL

Abstract

The one-electron (1e) oxidation of organic sulfides and methionine (Met) constitutes an important reaction mechanism in vivo.1,2 Evidence for a Cu(II)-catalyzed oxidation of Met35 in the Alzheimer’s disease ?-amyloid peptide was obtained,3 and, based on theoretical studies, Met radical cations were proposed as intermediates.4 In the structure of ?-amyloid peptide, the formation of Met radical cations appears to be facilitated by a preexisting close sulfur-oxygen (S-O) interaction between the Met35 sulfur and the carbonyl oxygen of the peptide bond C-terminal to Ile31.5 Substitution of Ile31 with Pro31 abolishes this S-O interaction,5 significantly reducing the ability of ?-amyloid to reduce Cu(II), and converts the neurotoxic wild-type ?-amyloid into a non-toxic peptide.6 The preexisting S-O bond characterized for wild-type ?-amyloid suggests that electron transfer from Met35 to Cu(II) is supported through stabilization of the Met radical cation by the electron-rich carbonyl oxygen, generating an S?O-bonded7 sulfide radical cation (Scheme 1, reaction 1).5