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William L. Smith
U of M Biological Chemistry

Biological Chemistry, Medical School
Areas of Interest
Our laboratory studies nutritionally essential fatty acids, prostaglandins and cyclooxygenases in inflammation, thrombosis and colon cancer. We are particularly interested in the regulation of cyclooxygenases by fish oil omega-3 fatty acids and by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and celecoxib.

Aspirin, ibuprofen, celebrex and other NSAIDs block the biosynthesis of prostaglandins by inhibiting the cyclooxygenases (COXs) that catalyze the first step in prostaglandin formation. Prostaglandins are formed from omega-6 and omega-3 polyunsaturated fatty acids, both of which are essential nutrients.

Prostaglandins function as "local" hormones that act at or near their sites of synthesis without traversing the circulation, to coordinate intra-organ physiological processes that typically involve the participation of two or more different cell types. One example is the interaction between blood platelets and vascular endothelial cells that occurs in hemostasis. Platelets produce a prostaglandin called thromboxane that causes platelet aggregation and vasoconstriction whereas the vasculature forms another prostaglandin called prostacyclin that counter-balances the effects of platelet-derived thromboxane. Aspirin is used to prevent coronary thrombosis because aspirin attenuates the overproduction of platelet thromboxane. A nutriceutical regimen that involves increased consumption of fish oil is also known to attenuate prostaglandin formation. Dietary fish oil may be useful in preventing colon cancer. We are collaborating with clinical investigators in the UM Cancer Center in addressing this topic.

At a more biochemical level, my group studies mechanistic aspects of COX-1 and COX-2. Over the years, our group was the first to purify and clone COX-1, to show that COX-1 and COX-2 are pharmacologically distinct, to delineate the molecular basis for the action of aspirin and to determine the x-ray structures of fatty acid substrates in the cyclooxygenase active site. Most recently, we have discovered that while COXs are homodimers based on primary sequence and crystal structures, they exhibit half sites activity--only one monomer catalyzes a COX reaction at any one time. Thus, COXs operate as conformational heterodimers.

Finally, we have been trying to understand why there is a need for two COX isoforms, and more specifically, how COX-2 can function independently of COX-1 when the isoforms are co-expressed in the same cell. Recently, we found that COX-1 and COX-2 function in different subcellular compartments.