FACULTY & STAFF
Lawrence M. Sayre
In Memoriam: July 25, 1951 - May 8, 2009
Please note, the Sayre group can no longer accept new students.
Frank Hovorka Professor of Chemistry
Professor of Pathology
Bioorganic and Pathophysiologic Chemistry
B.A., University of California at San Diego, 1972
Ph.D., University of California at Berkeley, 1977
Postdoctoral, University of Minnesota, 1979-81
CWRU Sigma Xi Research Award, 1988
NIH Research Career Development Award, 1987-92
Research in Professor Sayre's group focuses on the application of organic reaction mechanisms to selected problems in biology, some of which involve collaboration with scientists in the School of Medicine. There are two major areas of research.
Cofactor-Dependent Oxidations and Oxygenations, and the Development of Suicide Inhibitors: Amines constitute one of the most important classes of biologically active compounds. Amine-oxidizing enzymes utilize heme iron, copper, and/or organic redox cofactors to oxidize amines using an impressive range of different mechanisms. The quinone-dependent copper amine oxidases utilize a transamination mechanism to convert primary amines to aldehydes. Model quinone systems together with enzyme studies are being used to design mechanism-based inhibitors that are being synthesized and evaluated, and to define the chemistry of inactivation. Highly selective inhibitors being uncovered may be useful in intervening in disease conditions associated with dysregulation of human amine oxidases.
Verification of mechanism of inactivation and inhibitor selectivity is being addressed in part through collaborative studies to obtain X-ray crystal structures of enzyme-inhibitor complexes.
In a related project, we are also investigating, through model studies using the appropriate ligand systems, the role of copper in the biological activation of dioxygen by enzymes that carry out both oxidation chemistry (e.g., catechol oxidation to quinone) and oxygenation chemistry (e.g., aromatic and aliphatic hydroxylation). Of particular interest is the mechanism of biogenesis of the quino-cofactors used by copper amine oxidases.
Modification of Proteins in Aging and Degenerative Disease: Exposure of proteins to exogenous and endogenous reactive substances can result in abnormal protein function and consequent cytotoxicity. In collaboration with biomedical scientists, we are investigating (i) modification of low-density lipoprotein (LDL) by products of lipid peroxidation that occurs in atherosclerosis, (ii) protein oxidation and modification (by lipoxidation and glycoxidation products) in neurodegenerative diseases, in particular Alzheimer's disease, and (iii) protein oxidation and oxidative stress in aging. Of particular interest is the issue that modification, especially by bifunctional modifiers, can sometimes result in intramolecular and intermolecular crosslinking reactions, which can contribute to the poor proteolytic turnover of damaged proteins and thereby explain the formation of long-lived deposits.
This work involves a combination of chemical model studies that mimic the protein alterations, in vitro protein modification studies, and the development of immunochemical tools for analysis of particular protein lesions in biological fluids and tissues. Immunochemically-detected levels of specific oxidative stress markers in blood may be of diagnostic utility for pre-clinical diagnosis of disease. In addition, liquid chromatography mass-spectroscopic methods are being applied to the direct detection of oxidative stress adducts on proteins.
