Owen W. Griffith, PhD
Dr. Griffith obtained his Bachelor of Arts degree in Biochemistry from the University of California, Berkeley and his Doctorate degree from The Rockefeller University. The latter was awarded in 1975 for studies on the role of covalent enzyme-substrate intermediates in transferase reactions. Dr. Griffith's postdoctoral training was in the Department of Biochemistry, Cornell University Medical College, where he later joined the faculty in 1978 and achieved the rank of professor in 1987. In 1992, Dr. Griffith was appointed as Professor and Chairman of the Department of Biochemistry at the Medical College of Wisconsin, and he served in that capacity until 2001. At that time, Dr. Griffith stepped down as Chair to have more time to develop a biotech company he had helped start. In 2007, Dr. Griffith was appointed as Dean of the Graduate School of Biomedical Sciences. Dr. Griffith also remains a Professor of Biochemistry at the Medical College. His work continues to focus on the elucidation of enzyme mechanisms and the use of such information to design enzyme-specific substrates and inhibitors suitable for probing and controlling metabolic pathways in vivo.
Owen W. Griffith, PhD is a 2009 Distinguished Service Award Recipient.
Glutathione (L-g-glutamyl-L-cysteinylglycine, GSH), the main non-protein thiol in cells, plays a key role in defense against free radicals, peroxides, and electrophiles. We have made potent and specific inhibitors of GSH synthesis (e.g. buthionine sulfoximine, BSO) that cause GSH depletion in vivo. Studies with BSO and other inhibitors have defined the inter- and intra-organ pathways of GSH turnover and have elucidated the role of GSH in cell survival. BSO-mediated GSH depletion sensitizes tumor cells to alkylating agents, redox cycling drugs and radiation therapy. We have recently cloned and expressed human g-glutamylcysteine synthetase (g-GCS), the first and rate-limiting enzyme of GSH biosynthesis, and are exploring the chemical synthesis and mechanism of action of several novel inhibitors. We are also investigating the synthesis and use of novel g-GCS inhibitors directed at pathologic microbes (e.g., Streptococcus agalactiae). Inhibitors of the mechanistically related enzyme, glutamine synthetase, are of interest as possible anti-tuberculosis drugs.
In separate studies we are examining the enzymology, physiology and pharmacology of nitric oxide (NO), a free radical formed by five election oxidation of a guanidinium nitrogen of L-arginine. Cytokine-induced macrophages form large amounts of NO as part of their cytotoxic armament whereas endothelial cells form NO more slowly as a vascular smooth muscle relaxant and inhibitor of platelet aggregation and adhesion. We have prepared a series of N-substituted arginine analogs as inhibitors of NO synthesis and have begun to "map" the active sites of macrophage and endothelial cell NO synthase in order to design cell-type specific inhibitors. We have also developed novel non-amino acid inhibitors of the enzyme. In collaboration with other investigators, we have shown that (i) basal NO synthesis contributes to normal blood pressure homeostasis, (ii) NO synthesis can be limited by arginine availability, (iii) overproduction of NO accounts for the hypotension seen in septic (endotoxic) shock or seen following administration of tumor necrosis factor, interleukin-1a , or interleukin-2. The potentially lethal hypotension caused by septic shock or cytokine injection was reversed by giving NO synthesis inhibitors. Most recently, we have established that NO and its products have a direct inhibitory effects on GSH biosynthesis and have developed several isoform selective, irreversible NO synthase inhibitors.