Lipoxygenases (LOs): An Heterogenous Family of Lipid Peroxidizing Enzymes Implicated in Cell Differentiation, Inflammation, Asthma, Carcinogenesis, Atherogenesis-An Interesting Target for the Development of Promising Drugs

E.      Pontiki; D.      Hadjipavlou-Litina

doi:10.2174/157340805774580466

Abstract

Lipoxygenases (LOs) constitute a family of dioxygenases containing one non-heme iron atom per molecule, which oscillates between Fe2+ (inactive enzyme) and Fe3+ (active form) during the catalytic cycle. They catalyze the oxygenation of polyunsaturated fatty acids containing a (1Z, 4Z)-penta-1,4-diene system to the corresponding hydroxyperoxy derivatives. Arachidonic acid, which contains four double bonds in its configuration, is metabolised via lipoxygenases to a number of products with the hydroperoxy group in different positions. The LOs family includes several members which have been identified according the recommendations of the nomenclature committee of the international union of biochemistry and molecular biology on the nomenclature and classification of the enzymes by inserting oxygen into the 5-, 8-, 9-, 11-, 12- and 15- positions of fatty acids with varying stereoconfiguration (S or R). Four of these (5-LOs, 8-LOs, 12- LOs, 15-LOs) have been discovered in mammals to date. Although the cyclooxygenases could be considered specialized in the arachidonate pathway, the detailed mechanism of the LO reaction still remains controversial. It has been found that LOs are implicated in several processes such as cell differentiation, inflammation, carcinogenesis. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. Asthma consists the only pathological case in which improvement has been shown by LO inhibitors. The most widely studied isoform of the enzyme is 5-LO, which is involved in the biosynthesis of potent inflammatory mediators. Accordingly research efforts have been directed towards the development of drugs that interfere with the formation of leukotrienes. Zileuton (Zyflo) is the only 5-LO inhibitor on the market in the USA for the treatment of asthma.

Keywords: lipoxygenase, leukotrienes, asthma, arthritis, psoriasis, atherogenesis, substrate inhibitors, direct inhibitors, flap inhibitors