Professor, Biological Chemistry
Chair, Biological Chemistry
Minor J. Coon Professor of Biological Chemistry
B.A. University of Colorado
Ph.D. University of Michigan
Postdoctoral Fellow, University of California, Berkeley
Research Profile
Studies in my laboratory involve research on nutritionally essential fatty acids, prostaglandins, cyclooxygenases in thrombosis and colon cancer, and cyclooxygenase biochemistry including modulation by aspirin, ibuprofen, coxibs and fish oil.
Aspirin, ibuprofen, celebrex and other nonsteroidal anti-inflammatory drugs (NSAIDs) block the biosynthesis of prostaglandins by inhibiting the cyclooxygenases that catalyze the first step in prostaglandin formation. Prostaglandins are formed from omega-6 and omega-3 polyunsaturated fatty acids that 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 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 vasoconstriction and platelet aggregation whereas the vasculature forms a prostaglandin called prostacyclin that counter balances the effects of 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.
On the more biochemical level, my group studies the two cyclooxygenases (COXs) that catalyze the committed step in prostanoid biosynthesis. We are interested in learning how COX-1 and COX-2 function including how catalysis is modulated by interactions with NSAIDs, COX-2 inhibitors such as celebrex and fish oil fatty acids. 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 of sites activity--only one monomer catalyzes a cyclooxygenase reaction at any one time. Thus, COXs must be "conformational heterodimers" during catalysis; additionally, the binding of an NSAID to one of the two monomers completely inhibits COXs. We have also found that COX-2 inhibitors like celebrex, while not inhibiting COX-1 catalytic activity, do bind one subunit of COX-1 and interfere with the ability of the other monomer of COX-1 to be acetylated by aspirin. This finding is important clinically because it suggests that aspirin will not provide cardiovascular protection to patients taking COX-2 inhibitors like celebrex.
Awards
1981-1986 Am. Heart Association Established Investigator
1981 Faculty Teaching Award Osteopathic Medicine
1987-1995 NIH Merit Grant
1989 MSU Res. Excellence Award Golden Key Honorary Society
1991 Treadwell Award George Washington University
1992 Distinguished Faculty Award Michigan State University
1995-2003 NIH Merit Grant
1996 Abraham White Distinguished Scientific Achievement Award, George Washington University
1997 Senior Aspirin Award, Bayer Corporation
1999 Michigan Universities Assoc. of Governing Boards Award
2001-2003 University Distinguished Professor, MSU
2003-present University Distinguished Prof. Emeritus, MSU
2004 AAAS Fellow (Medical Sciences)
2004 State of Michigan Scientist of the Year Award
2004 Berzelius Lectureship, Karolinska Institute, Stockholm
2004 Avanti Award, American Soc of Biochemistry and Molecular Biology
2006 William C. Rose Award, American Soc of Biochemistry and Molecular Biology
2006 Hayaishi Lectureship, Hamamatsu University, Japan
2007 Olsen Lectureship, St. Louis University
PubMed Search Term : Smith+wl[au]+Michigan[affiliation]
Publications
Yuan, C., C.J. Rieke, G. Rimon, B.A. Wingerd, and W.L. Smith, Partnering between monomers of cyclooxygenase-2 homodimers, Proc. Nat. Acad. Sci. U.S.A. 103: 6142 - 6147, 2006. PMID: 16606823
Kang, Y-J., U.R. Mbonye, C.J. DeLong, M. Wada and W.L. Smith. Regulation of intracellular cyclooxygenase levels. Prog. Lipid Res., 46:108-125, 2007. PMID: 17316818
Wada, M., C.J. DeLong et al. Enzymes and receptors of prostaglandin pathways with arachidonic acid- vs. eicosapentaenoic acid-derived substrates and products. J. Biol. Chem., 282: 22254 - 22266, 2007. PMID: 17519235
Smith, W. L. Nutritionally Essential Fatty Acids and Biologically Indispensable Cyclooxygenases. TIBS, 33:7-37, 2008 PMID: 18155912
Mbonye, U.R., C. Yuan, C.E. Harris, R.S. Sidhu, I. Song, T. Arakawa and W.L. Smith. Two distinct pathways for cyclooxygenase-2 protein degradation. J. Biol. Chem., 283:8611-8623, 2008. PMID: 18203712