Bubb M R, Spector I, Bershadsky A D, Korn E D
Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 1995 Feb 24;270(8):3463-6. doi: 10.1074/jbc.270.8.3463.
Swinholide A, isolated from the marien sponge Theonella swinhoei, is a 44-carbon ring dimeric dilactone macrolide with a 2-fold axis of symmetry. Recent studies have elucidated its unusual structure and shown that it has potent cytotoxic activity. We now report that swinholide A disrupts the actin cytoskeleton of cells grown in culture, sequesters actin dimers in vitro in both polymerizing and non-polymerizing buffers with a binding stoichiometry of one swinholide A molecule per actin dimer, and rapidly severs F-actin in vitro with high cooperativity. These unique properties are sufficient to explain the cytotoxicity of swinholide A. They also suggest that swinholide A might be a model for studies of the mechanism of action of F-actin severing proteins and be therapeutically useful in conditions where filamentous actin contributes to pathologically high viscosities.
从海洋海绵斯氏海绵（Theonella swinhoei）中分离出的斯氏大环内酯A（Swinholide A）是一种具有44个碳原子的环状二聚体双内酯大环内酯，具有二重对称轴。最近的研究阐明了其独特的结构，并表明它具有强大的细胞毒性活性。我们现在报告，斯氏大环内酯A破坏培养细胞中的肌动蛋白细胞骨架，在体外聚合和非聚合缓冲液中隔离肌动蛋白二聚体，结合化学计量为每个肌动蛋白二聚体一个斯氏大环内酯A分子，并在体外以高协同性快速切断F-肌动蛋白。这些独特的特性足以解释斯氏大环内酯A的细胞毒性。它们还表明，斯氏大环内酯A可能是研究F-肌动蛋白切断蛋白作用机制的模型，并且在丝状肌动蛋白导致病理性高粘度的情况下可能具有治疗用途。
