Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Chariteplatz 1, D-10117 Berlin, Germany.
Indian Institute of Petroleum and Energy, Visakhapatnam 530003, Andhra Pradesh, India.
Biomed Pharmacother. 2022 Jan;145:112434. doi: 10.1016/j.biopha.2021.112434. Epub 2021 Nov 19.
Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.
脂氧合酶（ALOX-同工型）是脂质过氧化酶，它们与细胞分化和成熟有关，但也与脂质介质的生物合成有关，在炎症、过度增殖和神经疾病的发病机制中发挥着重要作用。在哺乳动物中，这些酶广泛分布，人类基因组涉及六个功能基因，编码六个不同的人 ALOX 同源物。在小鼠中，每种人类 ALOX 同源物都有一个同源酶，但人类和小鼠 ALOX 同源物的催化特性显示出显著差异。ALOX 抑制剂常用于在人类疾病的小鼠模型中阐明这些酶的生物学作用，但由于小鼠和人类 ALOX 同源物之间存在功能差异，因此不加批判地使用此类抑制剂有时会产生误导。在这项研究中，我们评估了 13 种常用的 ALOX 抑制剂对四种重组人源和鼠源 ALOX 同源物（ALOX15、ALOX15B、ALOX12、ALOX5）的同工型和同源型特异性，在不同的实验条件下。我们的结果表明，除了 zileuton 对小鼠和人源 ALOX5 具有显著的同工型特异性外，没有其他抑制剂是严格的同工型特异性的，但有些化合物具有有趣的同源型特异性。由于目前可用的 ALOX 抑制剂的亚型特异性不同，在解释这些化合物在复杂的体外和体内系统中观察到的生物学效应时必须谨慎。
