Inhibitor screening for human purine nucleoside phosphorylase, bovine xanthine oxidase and E. coli thymidine phosphorylase

CHED 726

Frida Fridman, ffridman@yu.edu1, Erika A. Taylor Ringia2, and Vern L. Schramm2. (1) Department of Chemistry, Stern College for Women, Yeshiva University, 245 Lexington Avenue, New York, NY 10016, (2) Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY
Characterization of the transition-state structures of enzymes involved in important biochemical pathways allows for the development of powerful inhibitors that may have medical applications. Three medicinally important enzymes involved in nucleoside metabolism: purine nucleoside phosphorylase (PNP), xanthine oxidase (XO) and thymidine phosphorylase (TP) have been interrogated with both transition-state analogue inhibitors and inhibitors based upon other design methods. PNP is recognized to be essential for proliferation of T-cells, thus it is a target for autoimmune disorders and T-cell malignancies. XO is involved in a metabolic pathway whose end product is uric acid, excess of which causes gout, and TP has recently been identified as an important factor in angiogenesis of many solid tumors. Identification of a potent inhibitor for these enzymes may lead to development of effective pharmaceuticals. Inhibitors designed by modeling the active site at the Institute of Molecular and Cellular Biology (France) were assayed against PNP and XO. Transition state analogue inhibitors synthesized by the National Institute of Health and Industrial Research Limited (New Zealand) were assayed against TP. Compounds found to have greater then 20% inhibition at a concentration of 10 mM were further analyzed and enzyme inhibition constants were calculated. Comparison of the inhibition specificity of these compounds leads to a greater comprehension of the mechanism, as well as leading to design and development of more specific inhibitors for the use as therapeutic agents.
 

Undergraduate Research Poster Session: Biochemistry
2:00 PM-4:00 PM, Monday, 27 March 2006 Georgia World Congress Center -- Ex. Hall B4, Poster

Division of Chemical Education

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006