Faculty

My research interests are directed toward understanding the chemical processes underlying the biosynthesis and functions of prostaglandins. Prostaglandins are oxygenated fatty acids that act as "local" hormones to coordinate physiological interactions between closely neighboring cells and cell types. Our current research is focused on understanding (a) the structural enzymology of prostaglandin endoperoxide H synthases (PGHSs) and (b) the regulation of PGHS gene expression. PGHSs are also known as "cyclooxygenases". There are two PGHS isozymes.

These enzymes catalyze the first step in prostaglandin formation--conversion of a twenty carbon polyunsaturated fatty acid called arachidonic acid to the prostaglandin endoperoxide H2 . At the more chemical level, we are studying the mechanism of the oxygenation reaction catalyzed by PGHSs and the biochemical pharmacology of PGHSs. This latter topic is important because PGHSs are the major targets of nonsteroidal anti-inflammatory compounds and COX-2 inhibitors (e.g. aspirin, ibuprofen, celebrex).

We are also performing studies to understand how the expression of the two PGHS genes are regulated. PGHS-2 is importantly involved in forming prostaglandins associated with inflammation and with colon cancer. PGHS-1 catalyzes the first step in thromboxane synthesis in platelet cells. Inhibition of platelet thromboxane production results in a diminished risk of cardiovascular mortality and is the basis for the use of low dose aspirin as a cardioprotective, anti-thrombogenic agent.

Awards

AAAS Fellow (Medical Sciences), 2004
State of Michigan Scientist of the Year Award, 2004
Avanti Award from the ASBMB, 2004
University Distinguished Professor Emeritus, Michigan State University, 2003-present
University Distinguished Professor, 2001-2003
NIH Merit Grant, 1995-2003
Michigan Universities Association of Governing Boards Award, 1999
Senior Aspirin Award, Bayer Corporation, 1997
Abraham White Distinguished Scientific Achievement Award, George Washington University, 1996
NIH Merit Grant, 1987-1995
Distinguished Faculty Award Michigan State University, 1992
Treadwell Award George Washington University, 1991
MSU Research Excellence Award Golden Key Honorary Society, 1989
American Heart Association Established Investigator, 1981-1986
Faculty Teaching Award Osteopathic Medicine, 1981
NIH Postdoctoral Fellow, 1971-1973

Representative Publications

1. Smith, W.L., DeWitt, D.L. and Garavito, R.M., "Cyclooxygenases: Cellular, Molecular and Structural Biology", Annu. Rev. Biochem., 2000, 69, 149.

2. Thuresson, E.D., Malkowski, M.G., Lakkides, K.M., Rieke, C.J., Mulichak, A.M., Ginell, S., Garavito, R.M. and Smith, W.L., "Mutational and X-ray Crystallographic Analysis of the Interaction of Dihomo-gamma-linolenic Acid with Prostaglandin Endoperoxide H synthases", J. Biol. Chem., 2001, 276, 10358.

3. Seibold, S.A., Ball, T., His, L.C., Mills, D.A., Abeysinghe, R.D., Micielli, R., Ricke, C.J., Cuker, C.I. and Smith, W.L., "Histidine 386 and its Role in Cyclooxygenase and Peroxidase Catalysis by Prostaglandin Endoperoxide H Synthases", J. Biol. Chem., 2003, 278, 46163.

4. Kuklev, D.V. and Smith, W.L., "Synthesis of Long Chain n-3 and n-6 Fatty Acids Having a Photoactive Conjugated Tetraene Group", Chem. Phys. Lipids, 2004, 130, 145.

5. Seibold, S.A., Smith, W.L. and Cukier, C.I., "The Peroxidase Site of Prostaglandin Endoperoxide H Synthase-1 Docking and Molecular Dynamic Studies with a Prostaglandin Endoperoxide Analog", J. Phys. Chem. B., 2004, 108, 9297.