Identification of novel myeloperoxidase-related products: Sphingolipid oxidation and o-oxidation of alpha-chlorinated fatty acids

Myeloperoxidase (MPO), an enzyme present in phagocytes, is involved in the pathogenesis of a variety of inflammatory diseases, including, atherosclerosis. The role of MPO as a marker of inflammation and adverse cardiac events is also expanding. MPO catalyzes the formation of reactive chlorinating species (RCS). MPO-derived RCS have been shown to oxidize a variety of compounds, including lipids. Oxidized lipid products are not only known to be proatherogenic, but these products and their metabolites also serve as markers of MPO activity. Our studies have led to the identification of novel MPO-related products. First, we studied MPO-derived RCS mediated oxidation of sphingolipids. We demonstrate that the sphingoid backbone in lysosphingolipids is susceptible to degradation and generates 2-hexadecenal. Furthermore, monochlorinated and chlorohydrin products of sphingolipids have been identified. The biological role of 2-hexadecenal was also elucidated. Next, we studied the o-oxidation of alpha-chlorinated fatty acids and identified the formation of alpha-chlorinated dicarboxylic acids. Similar to known dicarboxylic acids, the alpha-chlorinated dicarboxylic acids are water soluble and accumulate in the cell culture medium. Evidence for the biological relevance of this pathway is also presented. It is our belief that the identification of these products will aid in elucidation of the pathogenic role of MPO and provide novel candidate markers of MPO activity.