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The human genome involves six functional arachidonic acid (AA) lipoxygenase () 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.
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http://dx.doi.org/10.3390/ijms252212058 | DOI Listing |
Free Radic Biol Med
September 2025
Thrombosis Research Center, Universidad de Talca, Talca, 3460000, Chile; Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, 3460000, Chile. Electronic address:
Arachidonic acid metabolism through cyclooxygenase (COX) and lipoxygenase (LOX) pathways is fundamental to inflammation, vascular homeostasis, and neuronal signaling. Here, we investigated the roles of platelet-expressed COX (PTGS1) and LOX (ALOX12) isoforms in amyloid-β (Aβ) secretion, a process implicated in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Using an integrative approach combining bioinformatic protein-protein interaction mapping, pathway enrichment analysis, and experimental validation, we identified extensive networks linking PTGS and ALOX isoforms to cytoskeletal remodeling, mitochondrial function, and vesicle trafficking.
View Article and Find Full Text PDFJ Lipid Res
August 2025
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Biochemistry, Berlin, Germany. Electronic address:
Lipoxygenases (ALOX) convert free polyenoic fatty acids to bioactive mediators, which induce phenotypic alterations in target cells. However, the intracellular concentrations of free fatty acids are very low, as these compounds are rapidly esterified with coenzyme A. The acyl-CoA esters are subsequently used for re-acylation via the Lands cycle, or they are trans-esterified to acyl carnitines for mitochondrial import.
View Article and Find Full Text PDFCell Mol Biol Lett
July 2025
Department of Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Background: Mammalian arachidonic acid lipoxygenases (ALOXs) have previously been implicated in the pathogenesis of inflammatory disease, and pro- as well as anti-inflammatory activities have been reported. The human genome involves six functional ALOX genes and each of them encodes for a functionally distinct enzyme. ALOX15 is one of these isoforms and the majority of mammalian ALOX15 orthologs including mouse Alox15 convert arachidonic acid to its 12-hydroperoxy derivative.
View Article and Find Full Text PDFJ Lipid Res
April 2025
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Biochemistry, Berlin, Germany. Electronic address:
Arachidonic acid lipoxygenases (ALOXs) play important roles in cell differentiation and in the pathogenesis of cardiovascular, hyperproliferative, neurodegenerative, and metabolic diseases. The human genome involves six intact ALOX genes and knockout studies of the corresponding mouse orthologs indicated that the coding multiplicity of ALOX isoforms is not an indication for functional redundancy. Despite their evolutionary relatedness human and mouse ALOX15 and ALOX15B orthologs exhibit different catalytic properties.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, Vernadskogo pr. 86, Moscow 119571, Russia.