Functional modeling of the MnCAT active site with a dimanganese(III) complex of an unsymmetrical polydentate N 3 O 3 ligand

A new diMn III complex, [Mn 2 L(OAc) 2 (H 2 O)](BPh 4 )·3H 2 O (1), obtained with the unsymmetrical N 3 O 3 -ligand H 3 L = 1-[N-(2-pyridylmethyl),N-(2-hydroxybenzyl)amino]-3-[N′-(2-hydroxybenzyl),N′-(benzyl)amino]propan-2-ol, has been prepared and characterized. The unsymmetrical hexadentate ligand L 3− leads to coordination dissymmetry (dissimilar donor atoms) around each Mn ion (N 2 O 4 and NO 4 (solvent), respectively) leaving one labile site on one of the two Mn ions that facilitates interaction of the metal center with H 2 O 2 , as in Mn catalase. 1 is able to catalyze H 2 O 2 disproportionation in acetonitrile, with second-order rate constant k cat = 23.9(2) M −1 s −1 . The accessibility of the Mn II 2 state and the closeness of the two one-electron reduction processes suggest 1 employs Mn III 2 /Mn II 2 oxidation states for catalysis.Fil: Ledesma, Gabriela Nanci. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Anxolabehere Mallart, Elodie. Université Paris Diderot - Paris 7; FranciaFil: Sabater, Laurent. Universite de Toulouse; FranciaFil: Hureau, Christelle. Universite de Toulouse; FranciaFil: Signorella, Sandra Rosanna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentin

Role of Metal Ions in Alzheimer's Disease: Mechanistic Aspects Contributing to Neurotoxicity

International audienceMetal ions have long been linked to the etiology of Alzheimer's disease (AD) via a variety of mechanisms that mainly contribute to a worsening of the pathology. The present chapter proposes a state-of-the-art perspective about the toxic paths related to metal ions, mainly copper and zinc. Copper and zinc that are exchanged within the synaptic cleft can bind to the amyloid-β (Aβ) peptides, a key player in AD. This interaction has two main fallouts: the modulation of the self-assembly ability of the Aβ peptide leading to the formation of amyloid deposits and the production of reactive oxygen species contributing to the overall oxidative stress detected in AD. The molecular basis of these two main toxicity pathways will be described as well as their interrelation and their link with other factors

Redox processes in Cu-binding proteins: the “in-between” states in intrinsically disordered peptides

We report on a concept that some of us first described a decade ago for pure electron transfer [V. Balland, C. Hureau and J.-M. Savéant, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 17113]. In the present viewpoint, based on more recent results, we refine and extend this “in-between state” concept to explain the formation of reactive oxygen species by copper ions bound to the amyloid-β (Aβ) peptide involved in Alzheimer's disease. In such intrinsically disordered peptides, the Cu coordination is versatile due to the lack of stable folding and the presence of multiple possible binding anchors. Hence, the Cu(i) and Cu(ii) ions do impose their favoured sites, with Cu(i) bound in a linear fashion between two His residues and Cu(ii) in a square-based pyramid bound to Asp1 amine and carbonyl groups and two His residues in the equatorial plane. Hence a direct electron transfer is prevented and alternatively an in-between state (IBS) mechanism applies, whose description and analysis with respect to other electron transfer processes is the topic of the present viewpoint

Complexation du cuivre par les peptides impliqués dans les maladies neurodégénératives

International audienc

Reproducibility Problems of Amyloid-β Self-Assembly and How to Deal With Them

International audienceThe self-assembly of peptides and proteins into amyloid fibrils and other aggregates are linked to several diseases. One of the most studied cases is the peptide amyloid-β (Aβ), found self-assembled in Alzheimer's disease patients' brains. In test tubes, assays with chemically synthesized or recombinant Aβ are widely investigated to understand the aggregation process and to find modulators, which could be of therapeutic interest. Experience over more than a decade in our laboratory through discussions with colleagues, expertly studying the literature, and as reviewers revealed to us the widely encountered difficulty to control the aggregation and obtain reproducible results in the test tube. However, this issue is scarcely reported and discussed in the publications, which we think hampers strongly the progress in this field and can deceive newcomers. Here, we describe the difficulty and potential reasons to obtain reproducible aggregation data and propose some guidelines for working with it

Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 2: Dependence of Cu(II) binding sites with Aβ sequences

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Thermodynamic Study of Cu2+-Binding to the DAHK and GHK Peptides by Isothermal Titration Calorimetry (ITC) with the Weaker Competitor Glycine

The peptides Asp-Ala-His-Lys (DAHK) and Gly-His-Lys (GHK) are naturally occurring copper(II)-chelating motives in human serum and cerebrospinal fluid. Here the sensitive thermodynamic technique isothermal titration calorimetry (ITC) has been used to study the energetics of copper(II) binding to DAHK and GHK peptides in the presence of the weaker ligand glycine as a competitor. DAHK and GHK bind Cu(II) predominantly in a 1:1 stoichiometry with conditional dissociation constants (i.e. at pH 7.4, in the absence of the competing chelators glycine and HEPES buffer) of 2.6 +/- 0.4 x 10-14 M and of 7.0 +/- 1.0 x 10-14 M, respectively. Furthermore, the apparent ΔH values were measured and the number of protons released upon Cu(II) binding was determined by performing experiments in different buffers. This allowed us to determine the conditional ΔG, ΔH, and ΔS, i.e. corrected for the contributions of the weaker ligand glycine and the buffer at pH 7.4. We found that the entropic and enthalpic contributions to the Cu(II)-binding to GHK and DAHK are distinct, with a higher enthalpic contribution for GHK. The obtained thermodynamic parameters correspond well to those in the literature obtained by other techniques, suggesting that the use of the weaker ligand glycine as a competitor in ITC provides accurate data for Cu(II)-binding to high affinity peptides, which cannot be accurately determined without the use of a competitor ligand

Modélisation du centre de dégagement du dioxygène des plantes (synthèses chimique et électrochimique de complexes du manganèse)

Résumé français (1000 caractères maxi)Résumé anglais (idem)ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF