Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

https://hal.archives-ouvertes.fr/hal-01635507/document

Oxidative stress and the amyloid beta peptide in Alzheimer's disease.

Human serum albumin: from bench to bedside.

Protamines are the major nuclear sperm proteins. The human sperm nucleus contains two types of protamine: protamine 1 (P1) encoded by a single-copy gene and the family of protamine 2 (P2) proteins (P2, P3 and P4), all also encoded by a single gene that is transcribed and translated into a precursor protein. The protamines were discovered more than a century ago, but their function is not yet fully understood. In fact, different hypotheses have been proposed: condensation of the sperm nucleus into a compact hydrodynamic shape, protection of the genetic message delivered by the spermatozoa, involvement in the processes maintaining the integrity and repair of DNA during or after the nucleohistone-nucleoprotamine transition and involvement in the epigenetic imprinting of the spermatozoa. Protamines are also one of the most variable proteins found in nature, with data supporting a positive Darwinian selection. Changes in the expression of P1 and P2 protamines have been found to be associated with infertility in man. Mutations in the protamine genes have also been found in some infertile patients. Transgenic mice defective in the expression of protamines also present several structural defects in the sperm nucleus and have variable degrees of infertility. There is also evidence that altered levels of protamines may result in an increased susceptibility to injury in the spermatozoan DNA causing infertility or poor outcomes in assisted reproduction. The present work reviews the articles published to date on the relationship between protamines and infertility.

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Protamines and male infertility.

ion of hydrogen from the γ-(C-4) carbon of aliphatic side chains in the presence of oxygen can yield C-2 -C-3 dehydropeptides, via the formation of peroxyl radicals from the γ-carbon-centered radical. 208,210 For example, in the oxidation of the Glu side chain, the γ-carbon peroxyl radical may undergo subsequent reactions leading to the formation of side chain modification products with a mass shift of -30 Da due to decarboxylation; 209,211+14 and+16 Da products; or an unsaturated product, a C-2 -C-3 dehydropeptide (Scheme 4). The dehydropeptide behaves like an oxygenated enol species, which readily undergoes tautomerism to the keto form. This species is easily hydrolyzed to yield two protein fragments: a new amide and a keto acid. 210 Oxidation of aspartic acid seems similar to the case of Glu and may also result in the cleavage of the protein backbone 212 or decarboxylation of a side chain carboxyl group, 211 except at a lower rate than that for Glu. 211 3.2.4. Main Chain Cleavage via Radical Transfer from the â-Carbon at Side Chains Initial hydroxyl radical attack at theâ-carbon (C-3) position can lead to the formation of R-carbon radicals and subsequent main chain rupture. 213,214 In this case, alkoxyl radicals are generated after initial H-abstraction to produce carbon-centered radicals and subsequent reaction with O 2 o give peroxyl radicals (Scheme 5). A number of different pathways may generate alkoxyl radical from different precursors, including termination reactions of the peroxyl species with other radicals and decomposition of the intermediate hydroperoxides. 215,216The alkoxyl radicals can undergoâ-scission at a rate >107 s-1, leading to the loss of a side chain and/or generation of R-carbon radicals and subsequent backbone cleavage. 213,214 The â-scission reaction of alkoxyl radicals appears to be common for aliphatic side chains such as Val, Leu, and Asp,214 resulting in the release of a family of carbonyls including formaldehyde, acetone, isobutyraldehyde, and glyoxylic acids. The rate of suchâ-scission reactions is affected by the nature of the substituents, R and R ′, with the rate of fragmentation increased by the presence of electron releasing alkyl groups and substituents that can stabilize the incipient radical center. The R-carbon radicals generated by the â-scission reaction of alkoxyl radicals are stable due to the delocalization of unpaired electrons onto the neighboring carbonyl and amide functions and relief of steric strain in the alkoxyl radical. 217 Scheme 3. Backbone Cleavage and Side Chain Modification of Pro Hydroxyl Radical-Mediated Modification of Proteins Chemical Reviews, 2007, Vol. 107, No. 8 3527

Hydroxyl radical-mediated modification of proteins as probes for structural proteomics.

http://marcindyba.com/wp-content/uploads/publications/M_Dyba-Coord_Chem_Rev_1999_184_319-346.pdf

Specific structure–stability relations in metallopeptides

A comparative study of thermodynamic and kinetic aspects of Cu(II) and Ni(II) binding at the N-terminal binding site of human and bovine serum albumins (HSA and BSA, respectively) and short peptide analogues was performed using potentiometry and spectroscopic techniques. It was found that while qualitative aspects of interaction (spectra and structures of complexes, order of reactions) could be reproduced, the quantitative parameters (stability and rate constants) could not. The N-terminal site in HSA is much more similar to BSA than to short peptides reproducing the HSA sequence. A very strong influence of phosphate ions on the kinetics of Ni(II) interaction was found. This study demonstrates the limitations of short peptide modelling of Cu(II) and Ni(II) transport by albumins.

/pdf/short-peptides-are-not-reliable-models-of-thermodynamic-and-2qh86awyqg.pdf

Short peptides are not reliable models of thermodynamic and kinetic properties of the N‐terminal metal binding site in serum albumin

http://marcindyba.com/wp-content/uploads/publications/M_Dyba-J_Inorg_Biochem_2004_98_6_940-950.pdf

Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1-10, 1-16 fragments of human and mouse β-amyloid peptide

The review presents specific interactions that occur in complexes of Cu(II) ions with peptides composed only of amino acids with nonco-ordinating side chains. Three classes of such peptides are discussed. The first type (NSFRY analogues) is characterised by the presence of a specific combination of bulky and aromatic residues, leading to a formation of multiple weak interactions around Cu(II) that result in an extremely high stability of complexes. The second class is composed of complexes of vasopressins and oxytocins, achieving superstability through a pre-conformation in the peptide molecule. The third group are oligopeptides containing one or two proline residues. These peptides form exotic macrochelate loops with Cu(II) in a result of the break-point effect of Pro residues. Particular emphasis in the review was given to stability constants of complexes, compared to oligoglycine or oligoalanine peptides.

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The impact of the amino-acid sequence on the specificity of copper(II) interactions with peptides having nonco-ordinating side-chains.

Potentiometric and spectroscopic (EPR and absorption) studies have shown that two phosphonic groups bound to the same carbon atom serve as a very powerful binding site for Cu2+ ion in spite of the very high negative charge centred on these groups. The steric effects as well as a high negative charge enforce unusual geometries around the metal ion and the formation of 1:2 complexes is less favourable. These features of the diphosphonic moiety mean that alkoxo-bridged dimer formation via the adjacent hydroxyl groups is less likely.

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Marcin Dyba

Papers

Specific structure–stability relations in metallopeptides

Short peptides are not reliable models of thermodynamic and kinetic properties of the N‐terminal metal binding site in serum albumin

Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1-10, 1-16 fragments of human and mouse β-amyloid peptide

The impact of the amino-acid sequence on the specificity of copper(II) interactions with peptides having nonco-ordinating side-chains.

1-Hydroxyalkane-1,1-diyldiphosphonates as potent chelating agents for metal ions. Potentiometric and spectroscopic studies of copper(II) co-ordination