Owen W. Griffith, Ph.D.
Professor
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.
Contact Information
griffith@mcw.edu
Phone: (414) 456-8778
Fax: (414) 456-6510
Research Interests
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 homeostatasis, (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, inreversible NO synthase inhibitors.
Selected Publications
"Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalitites and Mortality in Patients with Cardiogenic Shock Following Acute Myocardial Infarction." S.J. Nicholls, Z. Wang, R. Koeth, B. Levison, B. DelFraino, V. Dzavik, O.W. Griffith, D. Hathaway, J.A. Panza, S.E. Nissen, J.S. Hochman and S.L. Hazen. Circulation 116, 2315-2324 (2007)
"y-Glutamylcysteine Synthetase-Glutathione Synthetase: Domain Structure and Indentification of Residues Important in Substrate and Glutathione Binding." B.E. Janowiak, M.A. Hayward, F.C. Peterson, B.F. Volkman and O.W. Griffith. Biochemistry 45, 10461-10473 (2006)
"Post-translational modification of manganese superoxide dismutase in acutely rejecting cardiac transplants: role of inducible nitric oxide synthase.", V. Nilakantan, N.L. Halligan, T.K. Nguyen, G. Hilton, A.K. Khannav, A.M. Roza, C.P. Johnson, M.B. Adams, O.W. Griffith, G.M. Pieper. J Heart Lung Transplant. 24: 1591-1599 (2005)
"Glutathione synthesis in Streptococcus agalactiae. One protein accounts for gamma-glutamylcysteine synthetase and glutathione synthetase activities.", B.E. Janowiak, O.W. Griffith. J Biol Chem, 280: 11829-11839 (2005)
"Variable efficacy of N6-(1-iminoethyl)-L-lysine in acute cardiac transplant rejection.", G.M. Pieper, V. Nilakantan, G. Hilton, X. Zhou, A.K. Khanna, N.L. Halligan, C.C. Felix, B. Kampalath, O.W. Griffith, M.A. Hayward, A.M. Roza, M.B. Adams. Am J Physiol Heart Circ Physiol, 286: H525-H534 (2004)
"Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes.", A. Brenot, K.Y. King, B. Janowiak, O.W. Griffith, and M.G. Caparon.
Infect Immun,
72: 408-413 (2004)
"Structural Characterization and Kinetics of Nitric-oxide Synthase Inhibition by Novel N5-(Iminoalkyl)- and N5-(Iminoalkenyl)-ornithines.", L.E. Bretscher, H. Li, T.L. Poulos, O.W. Griffith J Biol Chem, 278: 46789-46797 (2003)
"Non-heme iron protein: a potential target of nitric oxide in acute cardiac allograft rejection.", G.M. Pieper, N.L. Halligan, G. Hilton, E.A. Konorev, C.C. Felix, A.M. Roza, M.B. Adams, O.W. Griffith Proc Natl Acad Sci U S A, 100: 3125-3130 (2003)
"Glutaminase and the control of airway pH: yet another problem for the asthmatic lung?", O.W. Griffith Am J Respir Crit Care Med, 165(1): 1-2 (2002)
"Escherichia coli gamma-glutamylcysteine synthetase. Two active site metal ions affect substrate and inhibitor binding.", Kelly BS, Antholine WE, Griffith OW. J Biol Chem, 277 (1): 50-58 (2002)
"In vivo proton (H1) magnetic resonance spectroscopy for cervical carcinoma.", J.R. Allen, R.W. Prost, O.W. Griffith, S. J. Erickson, B. A. Erickson. Am J Clin Oncol, 24 (5): 522-529 (2001)
"Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase.", C.S. Raman, H. Li, P. Martasek, B.R. Babu, O.W. Griffith, B. S. Masters, T.L. Poulos. J Biol Chem, 276 (28): 26486-91 (2001)
"Chronic myocardial hypoxia increases nitric oxide synthase and decreases caveolin-3.", Y. Shi, K.A. Pritchard, Jr, P. Holman, P. Rafiee, O.W. Griffith, B. Kalyanaraman, J.E. Baker. Free Radic Biol Med, 29 (8): 695-703 (2000)
"Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increasing Nitric Oxide Production", J.E. Baker, P. Holman, B. Kalyanaraman, O.W. Griffith and K.A. Pritchard, Jr., Annals of the New York Academy of Sciences, 874: 236-253, (1999)
"L-Arginine Binding to Nitric Oxide Synthase: The Role of H-bonds to the Non-reactive Guanidinium Nitrogens", B.R. Babu, C. Frey and O.W. Griffith, Journal of Biological Chemistry, 274: 25218-25226 (1999)
"The Enzymes of Glutathione Synthesis: g-Glutamylcysteine Synthetase", O.W. Griffith and R.T. Mulcahy, Advances in Enzymology and Related Areas of Molecular Biology, 73: 209-267 (1999)
"Design of isoform-selective inhibitors of nitric oxidase synthase", B.R. Babu and O.W. Griffith, Current Opinion in Chemical Biology, 2: 491-500 (1998)
"Expression purification of human gamma-glutamylcysteine synthetase", I. Misra, O. W. Griffith, Protein Expression and Purification, 13: 268-276 (1998)
"N5-(1-Imino-3-butenyl)-L-ornithine. A neuronal isoform selective mechanism-based inactivator of nitric oxide synthase", B.R. Babu and O.W. Griffith, Journal of Biological Chemistry, 273: 8882-8889 (1998)
"Characterization of 5-oxo-L-prolinase in normal and tumor tissues of humans and rats: a potential new target for biochemical modulation of glutathione", X. Chen, R.L. Schecter, O.W. Griffith, M.A. Hayward, L.C. Alpert, and G. Batist. Clinical Cancer Research, 4: 131-138 (1998)
"L-amino acid oxidase (LOX) modulation of melphalan activity against intracranial glioma", K. Moynihan, G.B. Elion, C. Pegram, C.J. Reist, D. Wellner , D.D. Bigner, O.W. Griffith, and H.S. Friedman, Cancer Chemotherapy & Pharmacology, 39: 179-186 (1997)
"Measurements of total plasma nitrite and nitrate in pediatric patients with the systemic inflammatory response syndrome", L. Spack, P.L. Havens, and O.W. Griffith, Critical Care Medicine, 25: 1071-1078 (1997)
"Design of nitric oxide synthase inhibitors and their use to reverse hypotension associated with cancer immunotherapy", O.W. Griffith and R.G. Kilbourn. Advances in Enzyme Regulation, 37: 171-194 (1997)
"Inhibition of endothelial cell amino acid transport System y+ by arginine analogs that inhibit nitric oxide synthase", K.K. McDonald, R. Rouhani, M.E. Handlogten, E.R. Block, O.W. Griffith, R.D. Allison, and M.S. Kilberg, Biochimica et Biophysica Acta, 1324: 133-141 (1997)
"NO in septic shock: good, bad or ugly? Learning from iNOS knockouts", S.S. Gross, R.G. Kilbourn, and O.W. Griffith, Trends in Microbiology, 4: 47-49 (1996)
"Nitric oxide synthase: Characterization by electron paramagnetic resonance of the interactions of L-arginine and L-thiocitrulline with the heme cofactor region of nitric oxide synthase", J.C. Salerno, C. Frey, K. McMillian, R. Williams, B.S.S. Masters, and O.W. Griffith. Journal of Biological Chemistry, 270: 27423-27428 (1995)
"L-Thiocitrulline: A Stereospecific, Heme-Binding Inhibitor of Nitric Oxide Synthases", C. Frey, K. Narayanan, K. McMillan, L. Spack, S.S. Gross, B.S. Masters, and O.W. Griffith, Journal of Biological Chemistry, 269: 26083-26091 (1995)
"S-Alkyl-L-Thiocitrullines: Potent Stereoselective Inhibitors of Nitric Oxide Synthase with Strong Pressor Activity in Vivo", K. Narayanan, L. Spack, K. McMillan, R.G. Kilbourn, M.A. Hayward, B.S. Masters, and O.W. Griffith, Journal of Biological Chemistry, 270: 11103-11110 (1995)
"Nitric Oxide Synthases: Properties and Catalytic Mechanism", O.W. Griffith and D.J. Stuehr, Annual Review of Physiology, 57: 707-736 (1994)