Structural considerations on lipoxygenase function, inhibition and crosstalk with nitric oxide pathways

Abstract

Lipoxygenases (LOX) are non-heme iron-containing enzymes that catalyze regio- and stereo-selective dioxygenation of polyunsaturated fatty acids (PUFA). Mammalian LOXs participate in the eicosanoid cascade during the inflammatory response, using preferentially arachidonic acid (AA) as substrate, for the synthesis of leukotrienes (LT) and other oxidized-lipid intermediaries. This review focus on lipoxygenases (LOX) structural and kinetic implications on both catalysis selectivity, as well as the basic and clinical implications of inhibition and interactions with nitric oxide (^•NO) and nitroalkenes pathways. During inflammation ^•NO levels are increasingly favoring the formation of reactive nitrogen species (RNS). ^•NO may act itself as an inhibitor of LOX-mediated lipid oxidation by reacting with lipid peroxyl radicals. Besides, ^•NO may act as an O₂ competitor in the LOX active site, thus displaying a protective role on lipid-peroxidation. Moreover, RNS such as nitrogen dioxide (^•NO₂) may react with lipid-derived species formed during LOX reaction, yielding nitroalkenes (NO₂FA). NO₂FA represents electrophilic compounds that could exert anti-inflammatory actions through the interaction with critical LOX nucleophilic amino acids. We will discuss how nitro-oxidative conditions may limit the availability of common LOX substrates, favoring alternative routes of PUFA metabolization to anti-inflammatory or pro-resolutive pathways.

Keywords: Arachidonic acid; Free radicals; Lipoxygenases; Nitric oxide; Nitroalkenes; Nitroarachidonic acid; Structure-function relationship.