Understanding the mechanisms of protein modification
Our group works to understand the mechanisms of protein modification by reactive species (radicals, two-electron oxidants, glycation reactions), the biological consequences of such reactions, and the development of methods to quantify protein damage in disease with a particular emphasis on cardiovascular pathologies.
Furthermore, we are very interested in peroxidase enzymes (particularly myeloperoxidase), EPR spectroscopy for the detection of transient radicals, the kinetics of oxidant reactions, extracellular matrix damage and the development of antioxidants and inhibitors of oxidant formation.
Free radicals (reactive species with an unpaired electron) and other oxidants are generated in biological systems by both native processes (e.g. metabolic pathways and enzymes) and exposure to external events (UV and high-energy radiation, exposure to drugs, pollutants, mineral fibres, chemicals etc).
The damage induced by these oxidants has been linked to human disease, as well as changes in food quality and shelf life, agricultural yields and the quality and efficacy of medicines, vaccines and antibodies.
Under normal circumstances, the formation and reactions of oxidants are kept in check by multiple defensive and repair systems, including low-molecular-mass antioxidants, enzymes that scavenge oxidants or remove precursors, repair enzymes, and systems that remove irreversibly damaged materials.
Despite the number and range of these protective systems,there is considerable evidence for widespread oxidative damage in mammals, plants and micro-organisms, and for links between increased oxidation and multiple human diseases. This may arise from increased oxidant formation, a failure or decrease in defence systems, or both. This altered balance between formation and their removal / repair of oxidants, in favour of higher oxidant levels in often termed “oxidative stress”.
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Proteins are major targets for oxidation due to their abundance and rapid rates of reaction with oxidants. We want to understand in a quantitative and rigorous manner, the role of oxidants in protein damage, as such data will allow the rational and informed development of protective strategies against damage and disease.
A particular emphasis is being placed on protein oxidation and modification in cardiovascular disease, but the data obtained is also likely be of direct relevance to the pharmaceutical, food and hygiene industries, and agricultural production.
Protein oxidation has been detected at elevated levels on proteins present with human atherosclerotic lesions, the major underlying cause of most heart attacks and strokes. This damage is associated with increased morbidity and mortality, and has massive economic and social costs, but the processes that give rise to oxidation and the consequences of these reactions are poorly understood.
Prevention of oxidant damage in cardiovascular disease is in its infancy - many agents are being screened, but without adequate knowledge of the species involved and their reactions these efforts may not be well guided.
A key goal of our research is understanding the biochemical behaviour of oxidants associated with inflammation (e.g. hypochlorous acid, peroxynitrous acid, metal ions and radicals derived from these species) and elevated glucose levels (as seen in diabetes), and how these damage cells (endothelial, smooth muscle and macrophages) of relevance to cardiovascular disease, and their associated extracellular matrix.
These multidisciplinary projects are using a battery of tools including quantification of modified materials in human and animal tissues, cellular and animal studies, kinetic and mechanistic experiments, and computational chemistry. Such quantitative analysis is allowing the informed and rational development of novel preventive strategies.
Part of the research theme
Professor Michael Davies
D.Phil., C.Chem., FRACI
+ 45 23649445
Panum floor 12.6