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William L. Smith, Ph.D.

Professor, Biological Chemistry

B.A. University of Colorado
Ph.D. University of Michigan
Postdoctoral Fellow, University of California, Berkeley

Research Profile

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.

Awards

1981-1986 Am. Heart Association Established Investigator
1981 MSU 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
2012 Distinguished Faculty Lectureship, University of Michigan

PubMed Search Term : Smith+wl[au]+Michigan[affiliation]

Publications

Wada, M., T.L. Saunders, J. Morrow, G.L. Milne, K.P. Walker, S.K. Dey, T.G. Brock, M.R. Opp, D.M. Aronoff and W.L. Smith. Two pathways for cyclooxygenase-2 protein degradation in vivo. J. Biol. Chem. 284:30742-30753, 2009 PMID: 19758985 PMCID: PMC2781473

Rimon, G., R.S. Sidhu, D.A. Lauver, Lee, J.Y., Sharma, N.P., Yuan, C., Fieler, R.A., Trievel, R.C., Lucchesi, B.R. and Smith, W.L. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc. Nat. Acad. Sci. U.S.A., 107, 28-33, 2010 PMID: 19955429 PMCID: PMC2806742

Sharma, N.P., C. Yuan, L. Dong, K.R. Noon and W.L. Smith. Asymmetric acetylation of the cyclooxygenase-2 homodimer by aspirin and its effects on the oxygenation of arachidonic, eicosapentaenoic and docosahexaenoic acids. Mol. Pharmacol. 77, 979-986, 2010 PMID: 20194532 PMCID: PMC2879920

Sidhu, R.S., Lee, J.Y., Yuan, C. and Smith W.L. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers. Biochemistry, 49, 7069-7079, 2010. PMID:20669977 PMCID: PMC2932651

Dong, L., Vecchio, A.J., Sharma, N.P., Jurban, B.J., Malkowski, M.G. and Smith, W.L. Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer J. Biol. Chem., 286:19035 – 19046, 2011 PMID: 21467029 PMCID: PMC3099718

Neilson, A.P., Djuric, Z., Ren, J., Hong, Y.H., Sen, A., Lager, C., Jiang, Y., Reuven, S. Smith, W.L. and Brenner, D.E. Effect of cyclooxygenase genotype and dietary fish oil on colonic eicosanoids in mice. J Nutr. Biochem., 23: 966-976, 2012. PMID: 21937210 PMCID: PMC3246564

Zou, H., Yuan, C., Dong, L., Sidhu, R.S., Hong, Y.H., Kuklev, D., and Smith, W.L. Human cyclooxygenase-1 activity and its responses to COX inhibitors are allosterically regulated by nonsubstrate fatty acids. J. Lipid Res., 53:1336-1347, 2012. PMID: 22547204 PMCID: PMC3371245

Kuklev, D.V., Hankin, J.A., Uhlson, C.L., Hong, Y.H., Murphy, R.C. and Smith, W.L. Major urinary metabolites of 6-keto-prostaglandin F2α in mice J. Lipid Res., 54:1906 – 1914, 2013. PMID: 23644380 PMCID: PMC3679392

Dong, L., Sharma, N.P., Jurban, B.J. and Smith, W.L. Preexistent asymmetry in the human cyclooxygenase-2 homodimer. J. Biol. Chem. jbc.M113.505503. First Published on August 16, 2013, doi:10.1074/jbc.M113.505503

smithww@umich.edu

Office: 4301E MSRB3, Box 5606
PH: (734)647-3996

PubMed: Smith+wl[au]+Michigan[affiliation]

Laboratory Members:

Liang Dong
Holly Hong
Dmitry V. Kuklev
Chong Yuan
Hechang Zou

Department Affiliations

Chemical Biology Program