Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families.