Gündem Eda, Stehling Sabine, Borchert Astrid, Kuhn Hartmut
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Biochemistry, Berlin, Germany.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Biochemistry, Berlin, Germany.
J Lipid Res. 2025 Apr;66(4):100768. doi: 10.1016/j.jlr.2025.100768. Epub 2025 Mar 3.
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. Human ALOX15 oxygenates arachidonic acid mainly to 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid but 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid is the dominant oxygenation product of mouse Alox15. This functional difference is the results of a targeted enzyme evolution but the driving forces for this process have not been well defined. For human and mouse ALOX15B orthologs similar functional differences have been reported but for the time being it was unclear whether these differences might also be a consequence of targeted enzyme evolution. To address this question, we systematically searched the public databases for ALOX15B genes, expressed selected enzymes, and characterized their functional properties. We found that functional ALOX15B genes frequently occur in Prototheria and Eutheria but orthologous genes are rare in Metatheria. The vast majority of mammalian ALOX15B orthologs constitute arachidonic acid 15-lipoxygenating enzymes and this property did not depend on the evolutionary ranking of the animals. Only several Muridae species including M. musculus, M. pahari, M. caroli, M. coucha, and A. niloticus express arachidonic acid 8-lipoxygenating ALOX15B orthologs. Consequently, the difference in the reaction specificity of mouse and human ALOX15B orthologs may not be considered a functional consequence of targeted enzyme evolution.
花生四烯酸脂氧合酶（ALOXs）在细胞分化以及心血管疾病、增殖性疾病、神经退行性疾病和代谢性疾病的发病机制中发挥着重要作用。人类基因组包含六个完整的ALOX基因，对相应小鼠直系同源基因的敲除研究表明，ALOX同工型的编码多样性并不意味着功能冗余。尽管人类和小鼠的ALOX15及ALOX15B直系同源基因具有进化相关性，但它们表现出不同的催化特性。人类ALOX15主要将花生四烯酸氧化为15S - 氢过氧 - 5Z,8Z,11Z,13E - 二十碳四烯酸，但12S - 氢过氧 - 5Z,8Z,10E,14Z - 二十碳四烯酸是小鼠Alox15的主要氧化产物。这种功能差异是靶向酶进化的结果，但该过程的驱动力尚未明确界定。对于人类和小鼠的ALOX15B直系同源基因，也报道了类似的功能差异，但目前尚不清楚这些差异是否也是靶向酶进化的结果。为了解决这个问题，我们系统地在公共数据库中搜索ALOX15B基因，表达选定的酶，并表征它们的功能特性。我们发现功能性ALOX15B基因在原兽亚纲和真兽亚纲中频繁出现，但在有袋亚纲中直系同源基因很少见。绝大多数哺乳动物的ALOX15B直系同源基因构成花生四烯酸15 - 脂氧合酶，这一特性并不取决于动物的进化等级。只有包括小家鼠、帕哈里小鼠、卡罗小鼠、库查小鼠和尼罗多乳鼠在内的几种鼠科动物表达花生四烯酸8 - 脂氧合的ALOX15B直系同源基因。因此，小鼠和人类ALOX15B直系同源基因反应特异性的差异可能不能被视为靶向酶进化的功能结果。
