UC Santa Cruz

Research has shown that chronic inflammation is associated with many diseases such as cardiovascular disease, diabetes, cancer, and asthma. This chronic inflammation is caused by the failure of proper resolution of the inflammation overtime. Therefore, this dissertation explores the biosynthesis of lipoxygenase-derived products from DHA, drug discovery, and site-directed mutagenesis to determine the substrate and inhibitors binding to the lipoxygenase active site in order to understand how these pro-resolving molecules are made and help to guide for chronic disease therapy. The first chapter probes the electrostatic and steric requirements for substrate binding in human 12-LOX. The second chapter investigates the biosynthetic pathway of NPD1 and PDX by human lipoxygenase isozymes. The third chapter determines the dimeric interface of human 12-LOX by site-directed mutagenesis. The fourth and fifth chapters discover potent and selective inhibitors against human 12-LOX and 15-LOX-2 for thrombosis and atherosclerosis therapy.