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.
Honors & Awards
Distinguished Faculty Lectureship, University of Michigan, 2012
Olsen Lectureship, St. Louis University, 2007
Hayaishi Lectureship, Hamamatsu University, Japan, 2006
William C. Rose Award, ASBMB, 2006
Avanti Award, ASBMB, 2004
Berzelius Lectureship, Karolinska Institute, Stockholm, 2004
State of Michigan Scientist of the Year Award, 2004
Elected Fellow, American Association for the Advancement of Science, 2003
University Distinguished Professor Emeritus, Michigan State University, 2003–present
University Distinguished Professor, Michigan State University, 2001–2003
Michigan Universities Association of Governing Boards Award, 1999
Senior Aspirin Award, Bayer Corporation, 1997
Abraham White Distinguished Scientific Achievement Award, George Washington University, 1996
National Institutes of Health MERIT Award, 1995–2003
Distinguished Faculty Award, Michigan State University, 1992
Treadwell Award, George Washington University, 1991
Research Excellence Award, Golden Key Honor Society, Michigan State University, 1989
National Institutes of Health MERIT Award, 1987–1995
American Heart Association Established Investigator, 1981–1986
Faculty Teaching Award in Osteopathic Medicine, Michigan State University, 1981
Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin-E2 concentrations after dietary supplementation with ω-3 fatty acids.
Wilson MJ, Sen A, Bridges D, Turgeon DK, Brenner DE, Smith WL, Ruffin MT 4th, Djuric Z.
Prostaglandins Leukot Essent Fatty Acids. 2018; 139: 14-19.
Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6).
Cingolani G, Panella A, Perrone MG, Vitale P, Di Mauro G, Fortuna CG, Armen RS, Ferorelli S, Smith WL, Scilimati A.
Eur J Med Chem. 2017; 138: 661-68.
Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors.
Djuric Z, Aslam MN, Simon BR, Sen A, Jiang Y, Ren J, Chan R, Soni T, Rajendiran TM, Smith WL, Brenner DE.
J Nutr Biochem. 2017; 46: 90-99.
Fatty Acid Binding to the Allosteric Subunit of Cyclooxygenase-2 Relieves a Tonic Inhibition of the Catalytic Subunit.
Dong L, Yuan C, Orlando BJ, Malkowski MG, Smith WL.
J Biol Chem. 2016; 291: 25641-55.
Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2.
Dong L, Zou H, Yuan C, Hong YH, Uhlson CL, Murphy RC, Smith WL.
J Lipid Res. 2016; 57: 1043-50.
Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis.
Dong L, Zou H, Yuan C, Hong YH, Kuklev DV, Smith WL.
J Biol Chem. 2016; 291: 4069-78.
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