Reactivity of mammalian lipoxygenases (ALOX isoforms) with phospholipids, biomembranes and lipoproteins

Arachidonic acid lipoxygenases (ALOX-isoforms) have been implicated in cell differentiation and in the pathogenesis of various diseases. Human ALOX-isoforms prefer free polyunsaturated fatty acids as substrate but some of them are also capable of oxygenating complex ester lipids. Here we compared the reactivity of mammalian ALOX isoforms with complex lipid structures, explored the chemistry of the oxygenation products and characterized the structure of the enzyme-substrate complexes. We found that human and mouse ALOX15 orthologs as well as human ALOX15B are capable of oxidizing complex substates in the absence of adapter proteins and that the patterns of oxygenation products were similar to those of free fatty acid oxygenation. In contrast, the corresponding activities of mouse Alox15b and human ALOX12 were limited. Specific lipoxygenase products were also detected in the plasma lipids of mice with modified ALOX15 gene suggesting the in vivo activity of the enzyme on complex ester lipid substrates.