Department of Chemistry, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USA.
Structure. 2012 Sep 5;20(9):1490-7. doi: 10.1016/j.str.2012.06.003. Epub 2012 Jul 12.
Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 Å) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.
脂氧合酶是生物活性脂质家族生物合成中的关键酶，包括在炎症的起始和解决以及相关疾病（如糖尿病、心血管疾病和癌症）中具有重要作用的化合物。获得了白细胞 12-脂氧合酶催化结构域与同工型特异性抑制剂 4-(2-氧杂十五烷-4-炔基)苯丙酸（OPP）之间复合物的高分辨率（1.9 Å）晶体。在复合物的三维结构中，抑制剂占据了一个新的 U 形通道，该通道在一端向蛋白质表面开放，并延伸超过对于催化至关重要的氧化还原活性铁位。在模型中，该通道容纳了花生四烯酸，定义了催化反应底物的结合位点。在 OPP 结合位点旁边有一个空隙与酶的表面相连，为另一个底物氧气提供了一个合理的进入通道。
