Ascorbate Oxidation by Cu(Amyloid-β) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production

Elena Atrián-Blasco (1, 2) , Melisa del Barrio (1, 2) , Peter Faller (1, 3, 2) , Christelle Hureau (1, 2)

1 LCC - Laboratoire de chimie de coordination
2 Toulouse INP - Institut National Polytechnique (Toulouse)
3 Institut de Chimie de Strasbourg

Along with aggregation of the amyloid-β (Aβ) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Aβ is able to produce Reactive Oxygen Species (ROS) by the successive reductions of molecular dioxygen and the ROS such produced contribute to oxidative stress. In vitro, ROS production parallels the ascorbate consumption, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Aβ is moderate compared to other biomolecules, the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present article, we aim at determining the amounts of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidation, which mathematically corresponds to the rate at an infinite peptide to Cu ratio, i.e. without any contribution from peptide-unbound Cu. We show that for the wild-type Cu(Aβ) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examination of the dependence of the intrinsic rate of ascorbate oxidation, followed by UV-Vis spectroscopy, for several altered peptides, we determine some of the key residues that influence ROS production.

Domaines: Chimie de coordination; Biochimie [q-bio.BM]

Elena Atrián-Blasco, Melisa del Barrio, Peter Faller, Christelle Hureau. Ascorbate Oxidation by Cu(Amyloid-β) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production. Analytical Chemistry, 2018, 90 (9), pp.5909-5915. ⟨10.1021/acs.analchem.8b00740⟩. ⟨hal-01781841⟩