Structures of Leukotriene Biosynthetic Enzymes and Development of New Therapeutics

Abstract

Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.