Radiation induced oxidation of methionine-containing peptides
Krzysztof Bobrowski and Dariusz Pogocki
Department of Radiation Chemistry and Technology, Institute of
Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warszawa, Poland
The goal of our studies is to understand at the molecular level the chemical species and reactions induced by ionizing radiation in peptides containing thioether functions. Particular emphasis is put on characterizing short lived intermediates and understanding complex reactions mechanisms involved in oxidative radical processes, specially those involving interactions of the oxidised sulphur centre with neighbouring groups. Questions of a wide-ranging general interest concern the role of S-, N- and C-centred radicals generated in various oligopeptides containing methionine (Met) and relevant model compounds with respect to formation of 2c-3e bonds, redox processes, fragmentation and their mutual interconversion.
The current studies are focused on the potential function of Met residues as antioxidants or pro-oxidants and their role in radical-mediated oxidation of peptides and proteins in the biological environment and in molecular mechanisms during ageing and various neurodegenerative diseases. The pathogenesis of neurodegenerative diseases as Alzheimer’s disease and Creutzfeld-Jacob disease is strongly associated with the presence and depositions of amyloid b-peptide (bA) and prion protein (hPrP) in the brain. Both macromolecules contain Met-residue that makes them prone to oxidation and autooxidation processes. In order to achieve these goals the following topics will be realized: (i) influence of functional neighbouring groups and conformational flexibility of oligopeptides containing single and multiple Met residues, location and optical isomerism of Met residues on the oxidative reaction pathway (ii) diastereoselective oxidation of Met and Met-containing oligopeptides (iii) oxidation of relevant thioether model compounds through organic copper complexes. (iv) molecular modelling of amyloid b-peptide.
Experimental facilities of the Pulse Radiolysis Laboratory include: pulse radiolysis with time-resolved UV-VIS absorption spectroscopy conducted on 10-MeV linear electron accelerator (8 to 100 ns pulses) for studying fast chemical reactions initiated by radiation, analytical instrumentation employed for analysis of stable products formed during g-radiolysis (Dionex DX500 chromatograph system for ion chromatography (IC) and high-performance liquid chromatography (HPLC) and Shimadzu GC-14B gas chromatograph). Nanosecond laser flash photolysis based on Nd:YAG laser (with 4-5 ns pulses) is currently under construction. Complementary techniques are high-level quantum chemical calculations including ab initio and semi-empirical methods: molecular mechanics, molecular dynamics, Langevin dynamics, Gaussian 98 and 02, CHARMM and umbrella sampling.
Intramolecular sulfur-oxygen bond formation in radical cations of N-acetylmethionine
Free radicals of methionine in peptides: mechanism relevant to
b-amyloid oxidation and Alzheimer’s disease
Mutation of the Phe20 residue in Alzheimer’s amyloid
b-peptide might decrease its toxicity due to disruption of the
Met35-cupric site electron transfer pathway
COST P9 Workings group(s) of interest: WG3