Biomedical subjects

Dariusz Pogocki

Publications and source records attributed to Dariusz Pogocki.

7 recordsLinked to original sources

PubMed2006

EPR and DFT study on the stabilization of radiation-generated methyl radicals in dehydrated Na-A zeolite.

Electron paramagnetic resonance (EPR) spectroscopy was applied to study paramagnetic species stabilized in Na-A zeolite exposed to gaseous methane and gamma-irradiated at 77 K. Two types of EPR spectra were recorded during thermal annealing of zeolite up to room temperature. Owing to the results for the zeolite exposed to (13)CH(4) the multiplet observed at 110 K was assigned to a (.-)CH(3)...Na(+) complex. After decay of the multiplet, the isotropic quartet of methyl radical was recorded in the temperature range of 170-280 K. On the basis of the EPR parameters it is postulated that (.-)CH(3) radicals in this temperature region are able to freely rotate inside the zeolite cage. The structures of the (.-)CH(3)...Na(+) adsorption complex and respective hyperfine coupling constants were calculated by applying DFT quantum chemical methods. Two different models were applied to represent the zeolite framework: the 6T structure of one six-membered ring and the 3T cluster. The hyperfine coupling constants calculated for the (.-)CH(3)...Na(+) adsorption complex for both applied models show very good agreement with those obtained experimentally.

Computer Simulation↗

PubMed2006

EPR spectroscopy and theoretical study of gamma-irradiated asparagine and aspartic acid in solid state.

Aspartic acid (Asp) and asparagine (Asn) are vulnerable amino acids. One-electron addition or withdrawal reactions initiate many deleterious processes involving these amino acids. To study these redox processes we have irradiated by gamma-rays asparagine or aspartic acid in the solid state. The nature of the resulting free radicals was determined by electron paramagnetic resonance (EPR) and by calculations using DFT methods in various environments. Reactions initiated by electron transfer are different for both amino acids: Asn anion loses hydrogen atom whereas the cation undergoes decarboxylation. Conversely, Asp cation loses hydrogen atom from amine group, which triggers decarboxylation.

Asparagine↗

PubMed2004

Mutation of the Phe20 residue in Alzheimer's amyloid beta-peptide might decrease its toxicity due to disruption of the Met35-cupric site electron transfer pathway.

It has been proposed that the Met residue in the C-terminal domain of the Alzheimer's disease beta-amyloid peptide (betaA) serves as a source of electrons for the Cu(II)-catalyzed reduction of molecular oxygen to hydrogen peroxide. Mechanistically, this process would require the long distance electron transfer from the thioether sulfur to the peptide-bound copper. Therefore, the electron transfer pathways between the Met35 sulfur atom and the cupric site in the N terminus of betaA congeners have been analyzed applying semiclassical models of long distance electron transfer. Simulations performed for several betaA conformers collected along the 6 ns Langevin Dynamics trajectories suggest that the presence of the Phe20 residue in the peptide is required for feasibility of the electron transfer. Thus, I would like to propose the mutation Phe20Ala in betaA as a potential way to reduce its neurotoxicity.

Alzheimer Disease↗

PubMed2003

Free radical reactions of methionine in peptides: mechanisms relevant to beta-amyloid oxidation and Alzheimer's disease.

The pathogenesis of Alzheimer's disease is strongly associated with the formation and deposition of beta-amyloid peptide (beta AP) in the brain. This peptide contains a methionine (Met) residue in the C-terminal domain, which is important for its neurotoxicity and its propensity to reduce transition metals and to form reactive oxygen species. Theoretical studies have proposed the formation of beta AP Met radical cations as intermediates, but no experimental evidence with regard to formation and reactivity of these species in beta AP is available, largely due to the insolubility of the peptide. To define the potential reactions of Met radical cations in beta AP, we have performed time-resolved UV spectroscopic and conductivity studies with small model peptides, which show for the first time that (i) Met radical cations in peptides can be stabilized through bond formation with either the oxygen or the nitrogen atoms of adjacent peptide bonds; (ii) the formation of sulfur-oxygen bonds is kinetically preferred, but on longer time scales, sulfur-oxygen bonds convert into sulfur-nitrogen bonds in a pH-dependent manner; and (iii) ultimately, sulfur-nitrogen bonded radicals may transform intramolecularly into carbon-centered radicals located on the (alpha)C moiety of the peptide backbone.

Alzheimer Disease↗

PubMed2003

Alzheimer's beta-amyloid peptide as a source of neurotoxic free radicals: the role of structural effects.

This mini review gives a brief overview over the oxidation mechanism of methionine (Met), relevant for processes which may lead to the oxidation of amyloid beta-peptide (betaAP), involved in the pathogenesis of Alzheimer's disease. The Cu(II) -catalysed oxidation of C-terminal Met35 in betaAP depends on the secondary structure of the peptide. That seems to be the key to the known propensities of this peptide to form reactive oxygen species and free radicals. The pro-oxidant character of betaPAP is not associated with its beta-sheet insoluble form. On the contrary, the alpha-helically organised structure is responsible for betaAP redox-related cytotoxicity.

Alzheimer Disease↗

PubMed2002

Computational characterization of sulfur-cxygen-bonded sulfuranyl radicals derived from alkyl- and (carboxyalkyl)thiopropionic acids: evidence for sigma-type radicals.

Sulfide radical cations are known to stabilize via sulfur-oxygen bond formation with carboxylic acid functions. However, structural information on the resulting sulfuranyl radicals has so far only been provided by ESR spectroscopy for more stable, aromatic-substituted species, while the rather short-lived aliphatic sulfuranyl radicals have largely been characterized by time-resolved UV spectroscopy only. Therefore, we have obtained theoretical structural information on S-O-bonded sulfuranyl radicals from three model compounds, tert-butyl 2-(methylthio)peroxybenzoate, 3-methylthiopropionic acid, and 3,3'-thiodipropionic acid, using density functional theory, semiempirical, and molecular mechanics methods. All S-O-bonded species exist predominantly as three-electron-bonded sigma-radicals with an estimated heterolytic bond dissociation energy of the S therefore O bond on the order of 23-27 kcal mol(-1). Characteristic optical absorption bands, vibrational frequencies, and hyperfine coupling tensors are evaluated to facilitate the identification of such radicals by time-resolved UV, IR, and ESR spectroscopy.

Alkanes↗

PubMed2002

Redox properties of Met(35) in neurotoxic beta-amyloid peptide. A molecular modeling study.

The beta-amyloid peptide (betaAP) is the principal component of plaque associated with the pathology of Alzheimer's disease. Part of its neurotoxicity appears to correlate with the ability of the peptide to reduce Cu(II) and form free radicals. Both processes are dependent on the presence and oxidizability of Met(35) in the C-terminus of the peptide but no mechanistic details on the reactions leading to Met oxidation are known. On the basis of previous studies with model peptides, we hypothesize that a one-electron oxidation of Met(35) in betaAP is facilitated through a neighboring group effect. Complexed to Cu(II) and/or in a lipid-mimicking environment, the solution structure of betaAP includes a large alpha-helical part. The solution NMR structure of betaAP1-40 in aqueous SDS micelles reveals an alpha-helix between residues 27 and 36, containing Met(35). In this helical C-terminus of betaAP, the peptide bond C=O group C-terminal of Ile(31) is located very close to the Met(35) sulfur and could stabilize a Met(35) sulfide radical cation through formation of an (S-O) three-electron bond. In the present paper, we have computationally validated this hypothesis using Langevin dynamics methods to determine the collision frequency of the Met(35) thioether sulfur and the oxygen atoms of several peptide bonds in the betaAP sequence. Nanosecond time scale computations were carried out for four distinct betaAP congeners, betaAP26-40, betaAP26-36, betaAP26-40(Ile(31)Pro), betaAP40-26, and their respective Met(35)-sulfur-centered cation radicals. Here, betaAP26-40, betaAP26-40(Ile(31)Pro) and betaAP40-26 are representative fragments of the full length betaAP1-42 or betaAP42-1 sequence, respectively, whereas betaAP26-36 represents a unique betaAP sequence for which biological data are available. Initial structures of betaAP26-40, betaAP26-40(Ile(31)Pro), and betaAP26-36 were selected to be identical to that of the betaAP26-40 or betaAP26-36 sequence in full-length betaAP1-40. As the structures of betaAP40-26 and betaAP42-1 are not known, various initial conformations such as alpha-helix and antiparallel beta-sheet were selected for betaAP40-26. Our computational results show that betaAP26-40, representative for the same sequence in full-length betaAP1-42, has the highest tendency to form (S-O) bonds between Ile(31)C=O and Met(35)S. We conclude that native betaAP1-42 has a higher tendency to support Met(35) oxidation through (S-O) bond formation, consistent with the experimental observation that betaAP1-42 is more neurotoxic compared to the other investigated sequences.

Amino Acid Sequence↗