In this project, funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Libin Xu of the Department of Medicinal Chemistry at the University of Washington aims to develop chemical tools to understand the reactivities and reaction mechanisms of oxidation of biologically important lipids. Understanding the fundamental chemistry underneath lipid peroxidation has broad impacts because lipid peroxidation plays significant roles in human pathologies, such as aging, atherosclerosis, and degenerative diseases. The project lies at the interface of physical organic chemistry and bioorganic chemistry and utilizes modern analytical chemistry techniques, and is well suited to the education of scientists with different training backgrounds. This research group also aims to integrate education with the research plan by disseminating the knowledge of lipid peroxidation through outreach to high school students and teachers and attracting undergraduates from diverse backgrounds to the research field.
The rate-determining step in lipid peroxidation is the propagation step of the peroxyl radical, where generally two types of reactions occur: a) hydrogen-atom transfer from a donor to the peroxyl radical; b) peroxyl-radical addition to a carbon-carbon double bond. The hydrogen-atom transfer mechanism is well studied, but much less is known about the reactivities and products of peroxyl-radical addition reactions. The goal of this project is to elucidate factors governing the reactivity of peroxyl-radical addition to a double bond and the contribution of this mechanism to peroxidation of a number of biologically important lipids, including cholesterol biosynthetic precursors, fat-soluble vitamins, and polyunsaturated fatty acids. There are three research objectives: 1) Establish a "radical clock" to measure the rate constants of both hydrogen-atom transfer and peroxyl-radical addition; 2) Evaluate factors controlling the reactivities of peroxyl-radical addition to a double bond; 3) Elucidate the products and reaction mechanisms of free radical peroxidation of biologically important lipids.
