William L. Smith
Emeritus Professor

• B.A. 1967, University of Colorado
• Ph.D. 1971, University of Michigan
• NIH Postdoctoral Fellow, 1971-74, University of California, Berkeley
• Visiting Professor, 1985, Baylor College of Medicine
• Established Investigator, American Heart Association, 1981-86
• MSU Distinguished Faculty Award, 1992

smithww@msu.edu
Department of Biochemistry
Michigan State University
East Lansing, MI 48824-1319

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William L. Smith

Research Interests

Molecular Endocrinology Cellular Communication

Cell communication is necessary to coordinate biological events in higher organisms. Primary communication between organs is brought about by circulating hormones such as insulin and cortisol, which are produced by specialized endocrine tissues. Secondary communication, which is required for coordinating responses of different cell types comprising each organ, is the job of noncirculating, local hormones or autocoids. My research is devoted to characterizing the receptor signaling mechanisms used by autocoids. The autocoids we use for our studies are the prostaglandins (PGs). These compounds are importantly involved in the pathogenesis of coronary thrombosis, rheumatoid arthritis, and colon cancer. Thus, our studies are designed to yield basic information about autocoid function, while at the same time providing data of medical relevance.

Our current research is focussed on understanding the function of PGH synthases (cyclooxygenases) which catalyze the first step in prostaglandin formation -- conversion of arachidonic acid to the prostaglandin endoperoxide H₂. There are two PGH synthase isozymes. At the more chemical level, we are studying the enzymology and biochemical pharmacology of PGH synthases-1 and -2. This is important because these enzymes are the major pharmacological targets of nonsteroidal anti-inflammatory compounds. Using combinations of site-directed mutagenesis, amino acid-specific modifications, enzymological assays, and biophysical techniques, we are investigating (a) how arachidonic acid substrate and enzyme inhibitors (e.g., ibuprofen and aspirin) bind to the active site of the enzyme and (b) how a protein tyrosyl radical abstracts a hydrogen atom from arachidonate to initiate catalysis.

Recent studies in our laboratory indicate that PGH synthases-1 and -2 are associated with the endoplasmic reticulum and nuclear envelope, respectively. At the cell biological level, we are characterizing the manner in which PGH synthases are embedded in the membranes of the endoplasmic reticulum and nuclear envelope and how these two enzymes are targeted to their respective locations within cells. The nuclear location of PGH synthase-2 suggests that this enzyme may produce products that act within the nucleus during cell replication and differentiation. Accordingly, we are also determining whether there are nuclear receptors for prostaglandins.

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