Lipoxygenases - A Challenging Problem in Enzyme Inhibition and Drug Development

Abstract

Lipoxygenases (LOXs), cytochromes P450 (CYPs) and cyclooxygenases (COXs) catalyze peroxidation of unsaturated fatty acids. In humans they convert arachidonic acid into a variety of eicosanoids, which play a role in all inflammatory responses, cardiovascular and kidney diseases, Alzheimers, cancer and other ailments. Blocking one pathway can prompt the body to switch to the available alternatives. In contrast to CYP and COX, LOX has a non-heme iron co-factor. Several LOXs are produced or stress-induced in the human body. They share the same mechanism, but differ in sequence causing catalysis on the same substrate to be regio- and stereospecific. The action of 15-LOXs could be pro- or anti-inflammatory, and pro- or anticarcinogenic. Depending on the dose, LOXs inhibitors can induce or inhibit other oxygenases. Inhibition of these enzymes presents a great challenge in solving the problem of how to control their action and treat diseases, without causing severe side effects and maintaining/restoring a delicate equilibrium between them. Research on CYPs and COXs is more advanced, while studies of LOXs are lagging behind. This article presents a brief review about LOX structures and inhibition, their involvement in human diseases, and their interplay with other oxidoreductases. Keywords: Lipoxygenase, fatty acids, inhibition, structure, NSAIDs, regulation of oxygenases, eicosanoids in human diseases