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1.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068879

RESUMO

The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-ß peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated Aß sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu-Aß4-x] and [Cu-Aß1-x] complexes toward dopamine and other catechols. The results show that the CuII-ATCUN site is not redox-inert; the reduction of the metal is induced by coordination of catechol to the metal and occurs through an inner sphere reaction. The generation of a ternary [CuII-Aß-catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by reoxidation of the CuI complex. In addition to the N-terminal coordination site, the two vicinal histidines, His13 and His14, provide a second Cu-binding motif. Catechol oxidation studies together with structural insight from the mixed dinuclear complexes Ni/Cu-Aß4-x reveal that the His-tandem is able to bind CuII ions independently of the ATCUN site, but the N-terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of CuII bound to the secondary site.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , Dopamina/metabolismo , Oxirredutases/metabolismo , Peptídeos beta-Amiloides/química , Complexos de Coordenação/química , Cobre/química , Dopamina/química , Histidina/química , Histidina/metabolismo , Modelos Moleculares , Conformação Molecular , Oxirredução , Oxirredutases/química
2.
Inorg Chem ; 60(2): 606-613, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33405903

RESUMO

Interaction of copper ions with Aß peptides alters the redox activity of the metal ion and can be associated with neurodegeneration. Many studies deal with the characterization of the copper binding mode responsible for the reactivity. Oxidation experiments of dopamine and related catechols by copper(II) complexes with the N-terminal amyloid-ß peptides Aß16 and Aß9, and the Aß16[H6A] and Aß16[H13A] mutant forms, both in their free amine and N-acetylated forms show that efficient reactivity requires the oxygenation of a CuI-bis(imidazole) complex with a bound substrate. Therefore, the active intermediate for catechol oxidation differs from the proposed "in-between state" for the catalytic oxidation of ascorbate. During the catechol oxidation process, hydrogen peroxide and superoxide anion are formed but give only a minor contribution to the reaction.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Catecol Oxidase/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , Imidazóis/metabolismo , Peptídeos beta-Amiloides/síntese química , Peptídeos beta-Amiloides/química , Biocatálise , Catecol Oxidase/química , Complexos de Coordenação/química , Cobre/química , Imidazóis/química , Cinética , Estrutura Molecular , Oxirredução
3.
Molecules ; 25(21)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143109

RESUMO

The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aß40 constructs. This influence on peroxidase activity was also demonstrated using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aß16 and Aß40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aß40-hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aß16 and Aß40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aß on neurological disease progression.


Assuntos
Peptídeos beta-Amiloides/química , Benzotiazóis/química , Dopamina/química , Hemina/química , Fragmentos de Peptídeos/química , Peroxidases/química , Ácidos Sulfônicos/química , Humanos , Oxirredução
4.
Int J Mol Sci ; 21(20)2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33066163

RESUMO

We investigate the interaction of hemin with four fragments of prion protein (PrP) containing from one to four histidines (PrP106-114, PrP95-114, PrP84-114, PrP76-114) for its potential relevance to prion diseases and possibly traumatic brain injury. The binding properties of hemin-PrP complexes have been evaluated by UV-visible spectrophotometric titration. PrP peptides form a 1:1 adduct with hemin with affinity that increases with the number of histidines and length of the peptide; the following log K1 binding constants have been calculated: 6.48 for PrP76-114, 6.1 for PrP84-114, 4.80 for PrP95-114, whereas for PrP106-114, the interaction is too weak to allow a reliable binding constant calculation. These constants are similar to that of amyloid-ß (Aß) for hemin, and similarly to hemin-Aß, PrP peptides tend to form a six-coordinated low-spin complex. However, the concomitant aggregation of PrP induced by hemin prevents calculation of the K2 binding constant. The turbidimetry analysis of [hemin-PrP76-114] shows that, once aggregated, this complex is scarcely soluble and undergoes precipitation. Finally, a detailed study of the peroxidase-like activity of [hemin-(PrP)] shows a moderate increase of the reactivity with respect to free hemin, but considering the activity over long time, as for neurodegenerative pathologies, it might contribute to neuronal oxidative stress.


Assuntos
Hemina/química , Fragmentos de Peptídeos/química , Proteínas Priônicas/química , Sítios de Ligação , Oxirredução , Fragmentos de Peptídeos/metabolismo , Polimerização , Ligação Proteica
5.
Chem ; 6(3): 703-724, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32201749

RESUMO

The complex etiology of neurodegeneration continues to stifle efforts to develop effective therapeutics. New agents elucidating key pathways causing neurodegeneration might serve to increase our understanding and potentially lead to improved treatments. Here, we demonstrate that a water-soluble manganese(II) texaphyrin (MMn) is a suitable magnetic resonance imaging (MRI) contrast agent for detecting larger amyloid beta constructs. The imaging potential of MMn was inferred on the basis of in vitro studies and in vivo detection in Alzheimer's disease C. elegans models via MRI and ICP-MS. In vitro antioxidant- and cellular-based assays provide support for the notion that this porphyrin analog shows promise as a therapeutic agent able to mitigate the oxidative and nitrative toxic effects considered causal in neurodegeneration. The present report marks the first elaboration of an MRI-active metalloantioxidant that confers diagnostic and therapeutic benefit in Alzheimer's disease models without conjugation of a radioisotope, targeting moiety, or therapeutic payload.

6.
Inorg Chem ; 59(1): 274-286, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31820933

RESUMO

Tau protein is present in significant amounts in neurons, where it contributes to the stabilization of microtubules. Insoluble neurofibrillary tangles of tau are associated with several neurological disorders known as tauopathies, among which is Alzheimer's disease. In neurons, tau binds tubulin through its microtubule binding domain which comprises four imperfect repeats (R1-R4). The histidine residues contained in these fragments are potential binding sites for metal ions and are located close to the regions that drive the formation of amyloid aggregates of tau. In this study, we present a detailed characterization through potentiometric and spectroscopic methods of the binding of copper in both oxidation states to R1 and R3 peptides, which contain one and two histidine residues, respectively. We also evaluate how the redox cycling of copper bound to tau peptides can mediate oxidation that can potentially target exogenous substrates such as neuronal catecholamines. The resulting quinone oxidation products undergo oligomerization and can competitively give post-translational peptide modifications yielding catechol adducts at amino acid residues. The presence of His-His tandem in the R3 peptide strongly influences both the binding of copper and the reactivity of the resulting copper complex. In particular, the presence of the two adjacent histidines makes the copper(I) binding to R3 much stronger than in R1. The copper-R3 complex is also much more active than the copper-R1 complex in promoting oxidative reactions, indicating that the two neighboring histidines activate copper as a catalyst in molecular oxygen activation reactions.


Assuntos
Complexos de Coordenação/química , Cobre/química , Fragmentos de Peptídeos/química , Proteínas tau/química , Sítios de Ligação , Humanos , Conformação Molecular
7.
Inorg Chem ; 59(1): 900-912, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31869218

RESUMO

The combination between dyshomeostatic levels of catecholamine neurotransmitters and redox-active metals such as copper and iron exacerbates the oxidative stress condition that typically affects neurodegenerative diseases. We report a comparative study of the oxidative reactivity of copper complexes with amyloid-ß (Aß40) and the prion peptide fragment 76-114 (PrP76-114), containing the high-affinity binding site, toward dopamine and 4-methylcatechol, in aqueous buffer and in sodium dodecyl sulfate micelles, as a model membrane environment. The competitive oxidative and covalent modifications undergone by the peptides were also evaluated. The high binding affinity of Cu/peptide to micelles and lipid membranes leads to a strong reduction (Aß40) and quenching (PrP76-114) of the oxidative efficiency of the binary complexes and to a stabilization and redox silencing of the ternary complex CuII/Aß40/PrP76-114, which is highly reactive in solution. The results improve our understanding of the pathological and protective effects associated with these complexes, depending on the physiological environment.


Assuntos
Peptídeos beta-Amiloides/química , Cobre/química , Dopamina/química , Príons/química , Dodecilsulfato de Sódio/química , Sítios de Ligação , Humanos , Micelas , Conformação Molecular , Solubilidade
9.
Inorg Chem ; 58(14): 8995-9003, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247811

RESUMO

Recently, we reported on a series of aminomethylene-phosphonate (AMP) analogues, bearing one or two heterocyclic groups on the aminomethylene moiety, as promising Zn(II) chelators. Given the strong Zn(II) binding properties of these compounds, they may find useful applications in metal chelation therapy. With a goal of inhibiting the devastating oxidative damage caused by prion protein in prion diseases, we explored the most promising ligand, {bis[(1H-imidazol-4-yl)methyl]amino}methylphosphonic acid, AMP-(Im)2, 4, as an inhibitor of the oxidative reactivity associated with the Cu(II) complex of prion peptide fragment 84-114. Specifically, we first characterized the Cu(II) complex with AMP-(Im)2 by ultraviolet-visible spectroscopy and electrochemical measurements that indicated the high chemical and electrochemical stability of the complex. Potentiometric pH titration provided evidence of the formation of a stable 1:1 [Cu(II)-AMP-(Im)2]+ complex (ML), with successive binding of a second AMP-(Im)2 molecule yielding ML2 complex [Cu(II)-(AMP-(Im)2)2]+ (log K' = 15.55), and log ß' = 19.84 for ML2 complex. The CuN3O1 ML complex was demonstrated by X-ray crystallography, indicating the thermodynamically stable square pyramidal complex. Chelation of Cu(II) by 4 significantly reduced the oxidation potential of the former. CuCl2 and the 1:2 Cu:AMP-(Im)2 complex showed one-electron redox of Cu(II)/Cu(I) at 0.13 and -0.35 V, respectively. Indeed, 4 was found to be a potent antioxidant that at a 1:1:1 AMP-(Im)2:Cu(II)-PrP84-114 molar ratio almost totally inhibited the oxidation reaction of 4-methylcatechol. Circular dichroism data suggest that this antioxidant activity is due to formation of a ternary, redox inactive Cu(II)-Prp84-114-[AMP-(Im)2] complex. Future studies in prion disease animal models are warranted to assess the potential of 4 to inhibit the devastating oxidative damage caused by PrP.


Assuntos
Cobre/química , Isoxazóis/química , Príons/química , Tetrazóis/química , Modelos Moleculares , Oxirredução , Conformação Proteica
10.
ACS Chem Neurosci ; 10(1): 155-167, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30372021

RESUMO

The discovery of acetylcholine and acetylcholinesterase provided the first insight into the intricacies of chemical signal transduction and neuronal communication. Further elucidation of the underlying mechanisms led to an attendant leveraging of this knowledge via the synthesis of new therapeutics designed to control aberrant biochemical processes. The central role of the cholinergic system within human memory and learning, as well as its implication in Alzheimer's disease, has made it a point of focus within the neuropharmacology and medicinal chemistry communities. This review is focused on donepezil and covers the background, synthetic routes, structure-activity relationships, binding interactions with acetylcholinesterase, pharmacokinetics and metabolism, efficacy, adverse effects, and historical importance of this leading therapeutic in the treatment of Alzheimer's disease and true Classic in Chemical Neuroscience.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Donepezila/química , Donepezila/uso terapêutico , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Humanos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Relação Estrutura-Atividade
11.
Angew Chem Int Ed Engl ; 58(20): 6512-6527, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30536578

RESUMO

Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best-studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox-active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post-translational protein modification. Thus, protein-quinone modification is a heterogeneous process involving multiple DA-derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.


Assuntos
Dopamina/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Quinonas/uso terapêutico , Dopamina/farmacologia , Humanos , Estresse Oxidativo , Quinonas/farmacologia
12.
Inorg Chem ; 56(18): 11317-11325, 2017 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-28846410

RESUMO

Copper(II) binding to prion peptides does not prevent Cu redox cycling and formation of reactive oxygen species (ROS) in the presence of reducing agents. The toxic effects of these species are exacerbated in the presence of catecholamines, indicating that dysfunction of catecholamine vesicular sequestration or recovery after synaptic release is a dangerous amplifier of Cu induced oxidative stress. Cu bound to prion peptides including the high affinity site involving histidines adjacent to the octarepeats exhibits marked catalytic activity toward dopamine and 4-methylcatechol. The resulting quinone oxidation products undergo parallel oligomerization and endogenous peptide modification yielding catechol adducts at the histidine binding ligands. These modifications add to the more common oxidation of Met and His residues produced by ROS. Derivatization of Cu-prion peptides is much faster than that undergone by Cu-ß-amyloid and Cu-α-synuclein complexes in the same conditions.


Assuntos
Cobre/química , Estresse Oxidativo , Proteínas Priônicas/química , Catálise , Catecóis/química , Cobre/farmacologia , Peróxido de Hidrogênio/química , Cinética , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
13.
J Am Chem Soc ; 139(12): 4462-4476, 2017 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-28228011

RESUMO

Spectroscopic methods and density functional theory (DFT) calculations are used to determine the geometric and electronic structure of CuZ°, an intermediate form of the Cu4S active site of nitrous oxide reductase (N2OR) that is observed in single turnover of fully reduced N2OR with N2O. Electron paramagnetic resonance (EPR), absorption, and magnetic circular dichroism (MCD) spectroscopies show that CuZ° is a 1-hole (i.e., 3CuICuII) state with spin density delocalized evenly over CuI and CuIV. Resonance Raman spectroscopy shows two Cu-S vibrations at 425 and 413 cm-1, the latter with a -3 cm-1 O18 solvent isotope shift. DFT calculations correlated to these spectral features show that CuZ° has a terminal hydroxide ligand coordinated to CuIV, stabilized by a hydrogen bond to a nearby lysine residue. CuZ° can be reduced via electron transfer from CuA using a physiologically relevant reductant. We obtain a lower limit on the rate of this intramolecular electron transfer (IET) that is >104 faster than the unobserved IET in the resting state, showing that CuZ° is the catalytically relevant oxidized form of N2OR. Terminal hydroxide coordination to CuIV in the CuZ° intermediate yields insight into the nature of N2O binding and reduction, specifying a molecular mechanism in which N2O coordinates in a µ-1,3 fashion to the fully reduced state, with hydrogen bonding from Lys397, and two electrons are transferred from the fully reduced µ4S2- bridged tetranuclear copper cluster to N2O via a single Cu atom to accomplish N-O bond cleavage.


Assuntos
Cobre/metabolismo , Marinobacter/enzimologia , Oxirredutases/metabolismo , Teoria Quântica , Biocatálise , Dicroísmo Circular , Cobre/química , Espectroscopia de Ressonância de Spin Eletrônica , Ligação de Hidrogênio , Cinética , Oxirredutases/química
14.
Chemistry ; 22(47): 16964-16973, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27735097

RESUMO

The oxidative reactivity of copper complexes with Aß peptides 1-16 and 1-28 (Aß16 and Aß28) against dopamine and related catechols under physiological conditions has been investigated in parallel with the competitive oxidative modification undergone by the peptides. It was found that both Aß16 and Aß28 markedly increase the oxidative reactivity of copper(II) towards the catechol compounds, up to a molar ratio of about 4:1 of peptide/copper(II). Copper redox cycling during the catalytic activity induces the competitive modification of the peptide at selected amino acid residues. The main modifications consist of oxidation of His13/14 to 2-oxohistidine and Phe19/20 to ortho-tyrosine, and the formation of a covalent His6-catechol adduct. Competition by the endogenous peptide is rather efficient, as approximately one peptide molecule is oxidized every 10 molecules of 4-methylcatechol.


Assuntos
Peptídeos beta-Amiloides/química , Catecóis/química , Cobre/química , Cromatografia Líquida de Alta Pressão , Complexos de Coordenação/química , Cinética , Oxirredução
15.
Molecules ; 21(8)2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27517887

RESUMO

The importance of understanding interactomes makes preeminent the study of protein interactions and protein complexes. Traditionally, protein interactions have been elucidated by experimental methods or, with lower impact, by simulation with protein docking algorithms. This article describes features and applications of the BiGGER docking algorithm, which stands at the interface of these two approaches. BiGGER is a user-friendly docking algorithm that was specifically designed to incorporate experimental data at different stages of the simulation, to either guide the search for correct structures or help evaluate the results, in order to combine the reliability of hard data with the convenience of simulations. Herein, the applications of BiGGER are described by illustrative applications divided in three Case Studies: (Case Study A) in which no specific contact data is available; (Case Study B) when different experimental data (e.g., site-directed mutagenesis, properties of the complex, NMR chemical shift perturbation mapping, electron tunneling) on one of the partners is available; and (Case Study C) when experimental data are available for both interacting surfaces, which are used during the search and/or evaluation stage of the docking. This algorithm has been extensively used, evidencing its usefulness in a wide range of different biological research fields.


Assuntos
Algoritmos , Simulação de Acoplamento Molecular , Proteínas/química , Proteínas/metabolismo , Proteínas/genética
16.
Inorg Chem ; 55(12): 6100-6, 2016 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-27259006

RESUMO

α-Synuclein (αS) is the main protein component of Lewy bodies, characterizing the pathogenesis of Parkinson's disease. αS is unstructured in solution but adopts a helical structure in its extended N-terminal segment upon association with membranes. In vitro the protein binds avidly Cu(II), but in vivo the protein is N-acetylated, and Cu(II) binding is lost. We have now clarified the binding characteristics of the Cu(I) complex with the truncated αS peptide 1-15, both in N-acetylated and free amine forms, in a membrane mimetic environment and found that complexation occurs with a 1:2 Cu(I)-αS stoichiometry, where Cu(I) is bound to Met1 and Met5 residues of two helical peptide chains. The resulting tetrahedral Cu(I) center is redox-stable, does not form reactive oxygen species, and is unreactive against dopamine in the presence of O2. This suggests that, unlike cytosolic Cu(I)-αS, which retains the capacity to activate O2 and promote oxidative reactions, membrane-bound Cu(I)-αS may serve as a sink for unreactive copper.


Assuntos
Cobre/química , Peptídeos/química , alfa-Sinucleína/química , Oxirredução
17.
J Inorg Biochem ; 163: 292-300, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27112900

RESUMO

Parkinson's disease (PD) is a severe neurodegenerative disorder affecting movements. After Alzheimer's disease, it is the most common form of neurodegeneration. PD is characterized by the loss of neurons producing dopamine and by the presence of protein aggregates in the brain, known as Lewy bodies. The main constituent of Lewy bodies is the misfolded form of α-synuclein (αSyn), able to form oligomers and fibrils. In addition to protein aggregation, brain damage induced by oxidative stress, is also a frequent phenomenon in PD. αSyn is able to bind Copper ions in both Cu(II) and Cu(I) oxidation states. The metal binding is also maintained when αSyn interacts with membranes. Interestingly, copper binding to αSyn has strong impact either in protein misfolding or in free radical formation, such to provide a link between protein aggregation and oxidative damage. In this review the role of copper and αSyn in PD is discussed with a particular emphasis to elucidate (i) the interaction between copper and αSyn; (ii) the reactivity and (iii) potential toxicity associated with copper-αSyn complexes.


Assuntos
Doença de Alzheimer/metabolismo , Cobre/metabolismo , Estresse Oxidativo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Doença de Alzheimer/genética , Animais , Humanos , Oxirredução , Doença de Parkinson/genética
18.
Chem Sci ; 6(10): 5670-5679, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26417423

RESUMO

Spectroscopic and computational methods have been used to determine the protonation state of the edge sulfur ligand in the Cu4S2 CuZ form of the active site of nitrous oxide reductase (N2OR) in its 3CuICuII (1-hole) and 2CuI2CuII (2-hole) redox states. The EPR, absorption, and MCD spectra of 1-hole CuZ indicate that the unpaired spin in this site is evenly delocalized over CuI, CuII, and CuIV. 1-hole CuZ is shown to have a µ2-thiolate edge ligand from the observation of S-H bending modes in the resonance Raman spectrum at 450 and 492 cm-1 that have significant deuterium isotope shifts (-137 cm-1) and are not perturbed up to pH 10. 2-hole CuZ is characterized with absorption and resonance Raman spectroscopies as having two Cu-S stretching vibrations that profile differently. DFT models of the 1-hole and 2-hole CuZ sites are correlated to these spectroscopic features to determine that 2-hole CuZ has a µ2-sulfide edge ligand at neutral pH. The slow two electron (+1 proton) reduction of N2O by 1-hole CuZ is discussed and the possibility of a reaction between 2-hole CuZ and O2 is considered.

19.
Chembiochem ; 16(16): 2319-28, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26338312

RESUMO

Copper binding to α-synuclein (aS) and to amyloid-ß (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ⋅ peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, ß-synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu(I) ligand. We found that: 1) the peptides containing the Cu-binding domains Ab1-16, aS1-15 and bS1-15 have similar affinities towards Cu(II) and towards Cu(I), with Ab1-16 being slightly stronger, 2) in the case of Cu(I), the additional Met residue in bS1-15 increased the affinity slightly, 3) the exchange of Cu(I/II) between the two peptides is rapid (≤ ms), 4) a/bS1-15 and Ab1-16 form a heterodimeric complex with Cu(II), 5) Cu(I) probably promotes a transient ternary complex, 6) the different Cu(I/II) coordination of Ab1-16, aS1-15 and bS1-15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1-16, aS1-15 and Cu are present, the ROS production more closely resembles that by Ab1-16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.


Assuntos
Peptídeos beta-Amiloides/química , Cobre/química , alfa-Sinucleína/química , beta-Sinucleína/química , Peptídeos beta-Amiloides/metabolismo , Ácido Ascórbico/química , Sítios de Ligação , Catálise , Complexos de Coordenação/química , Cobre/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Cinética , Ressonância Magnética Nuclear Biomolecular , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , alfa-Sinucleína/metabolismo , beta-Sinucleína/metabolismo
20.
Inorg Chem ; 54(10): 4744-51, 2015 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-25926427

RESUMO

Parkinson's disease (PD) etiology is closely linked to the aggregation of α-synuclein (αS). Copper(II) ions can bind to αS and may impact its aggregation propensity. As a consequence, deciphering the exact mode of Cu(II) binding to αS is important in the PD context. Several previous reports have shown some discrepancies in the description of the main Cu(II) site in αS, which are resolved here by a new scenario. Three Cu(II) species can be encountered, depending on the pH and the Cu:αS ratio. At low pH, Cu(II) is bound to the N-terminal part of the protein by the N-terminal amine, the adjacent deprotonated amide group of the Asp2 residue, and the carboxylate group from the side chain of the same Asp2. At pH 7.4, the imidazole group of remote His50 occupies the fourth labile equatorial position of the previous site. At high Cu(II):αS ratio (>1), His50 leaves the coordination sphere of the first Cu site centered at the N-terminus, because a second weak affinity site centered on His50 is now filled with Cu(II). In this new scheme, the remote His plays the role of a molecular switch and it can be anticipated that the binding of the remote His to the Cu(II) ion can induce different folding of the αS protein, having various aggregation propensity.


Assuntos
Cobre/química , Peptídeos/química , alfa-Sinucleína/química , Ácido Aspártico/química , Sítios de Ligação , Espectroscopia de Ressonância de Spin Eletrônica , Histidina/química , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Peptídeos/síntese química , Agregados Proteicos , Ligação Proteica , Dobramento de Proteína , Técnicas de Síntese em Fase Sólida
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