SUPEROXIDE PRODUCTION IN RESPIRATORY ELECTRON TRANSPORT MINIMIZATION AND UTILIZATION By ISAAC PAUL FORQUER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY

by ISAAC PAUL FORQUER Washington State University December 2008 Chair: David M. Kramer The oxidation of ubiquinol by the cytochrome bc1 complex is usually a tightly controlled process, however there are instances when the reaction is compromised by mutation or other external factors such as inhibitors that leads to superoxide production. The first part of this dissertation compares the electron transfer reactions between when the enzyme is performing efficiently and when superoxide production is taking place. The results of this section suggest that the same rate limiting step governs the two reactions, which allows for the elimination of several models explaining these critical reactions. The second part of this thesis deals with the electron transport chain of mitochondria in Plasmodium spp., the causative protozoan of malaria. First, it was hypothesized that a series of modified acridones were inhibitors of the cytochrome bc1 complex in Plasmodium spp. To validate the target of these compounds, they were tested first to see if in fact they inhibited the enzyme in mitochondrial extracts of Plasmodium yoelli. Then to conduct more detailed studies, the compounds were tested against the cytochrome bc1 complex from rat heart tissue. The results showed that acridones with an alkyl tail in the 3-position of the main ring were 1. potent inhibitors of the enzyme and 2. inhibited the site of ubiquinol oxidation.