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Recent advances in the cloning and characterization of eicosanoid (prostaglandins, leukotrienes) pathway enzymes (cyclooxygenases (COX), lipoxygenases) and receptors have provided new structural, functional and genetic information as well as novel therapeutic targets. First eicosanoid pathway modulators like COX-2 inhibitors and Cys-leukotriene receptor antagonists have already found important places in the therapies of arthritis, pain and asthma. The central theme of this application involves further characterization of novel invertebrate cyclooxygenases and lipoxygenases, recently cloned and expressed by our group. We use these ancestral enzymes as models to investigate the aspects of dioxygenase catalysis that are still poorly understood: control of oxygenation regio- and stereospecificity, impact of the peroxidase activity on ¿sparking¿ and maintenance the cyclooxygenase reaction, effect of the N-glycosylation pattern on the COX catalytic activity, and evolutionary divergence of COX gene. These studies will develop new insights into the mechanisms and regulation of mammalian dioxygenases and as a consequence have practical benefits in development of new isozyme specific therapeutics. |