In recent years functional genomics of eicosanoid synthesizing enzymes and molecular enzymology of these biocatalysts have become a hotspot in eicosanoid research. One reason for this switch in interest is the fact that rational drug development requires detailed knowledge on structural biology of enzymes and receptors to effectively prevent their interactions with the natural ligands.
The present research project is aimed at assembling a comprehensive picture of lipoxygenase/cyclooxygenase catalysis employing dynamic models. To understand the fundamental principles of the enzymatic reaction we will combine biochemical and molecular biological approaches and use them for investigation of elementary steps of the reaction cascades with particular emphasis on the substrate binding and intra-enzyme oxygen movement.
Structurally, the project can be divided into three subprojects:
i) substrate binding of mammalian LOX/COX-isoforms;
ii) investigations of solution structure of LOX/COX-isoforms; inter-domain movement in LOXs and its regulatory relevance;
iii) structural identification of oxygen access channel(s) applying an integrated research strategy that involves molecular modelling (structural modelling and molecular dynamics) and site-directed mutagenesis.
Eicosan oids and eicosanoid synthesizing enzymes have been implicated in the pathogenesis of atherosclerosis, inflammation, osteoporosis and cancer, which are of major health political relevance for all industrialized countries. Our results are expected to open new perspectives in regulation of catalytic activity of LOX/COX-isoforms providing an improved structural basis for the development of novel therapeutics.
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