Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria
Mechanism of action of tubulysin, an antimitotic peptide from myxobacteria
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DOI：
10.1002/cbic.200500421
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发表时间：
2006-04-01
期刊：
影响因子：
3.2
通讯作者：
Reichenbach, H
中科院分区：
文献类型：
--
作者：
Khalil, MW;Sasse, F;Reichenbach, H
微管溶素A是一种具有抗有丝分裂活性的高细胞毒性肽，其诱导细胞微管耗尽并触发凋亡过程。处理的细胞在G（2）/M期聚集。微管溶素A比长春碱更有效地抑制微管蛋白聚合，并诱导分离的微管制剂的解聚。无论是在无细胞系统还是在细胞系中，用埃坡霉素B和紫杉醇预孵育都不能防止微管解聚。在竞争实验中，微管溶素A以非竞争方式强烈干扰长春碱与微管蛋白的结合，相反的Ki为3 μ m。电子显微镜研究表明，微管溶素A诱导形成的环，双环，和风车结构。微管溶素A的作用模式类似于肽类抗有丝分裂剂dolostatin 10、视黄质A和hemiasterlin。正在努力开发这组新的化合物作为抗癌药物。
Tubulysin A is a highly cytotoxic peptide with antimitotic activity that induces depletion of cell microtubules and triggers the apoptotic process. Treated cells accumulated in the G(2)/M phase. Tubulysin A inhibited tubulin polymerization more efficiently than vinblastine and induced depolymerization of isolated microtubule preparations. Microtubule depolymerizotion could not be prevented by preincubation with epothilone B and paclitaxel, neither in cell-free systems nor in cell lines. In competition experiments, tubulysin A strongly interfered with the binding of vinblastine to tubulin in a noncompetitive way; the opporent K-i was 3 mu m. Electron microscopy investigations showed that tubulysin A induced the formation of rings, double rings, and pinwheel structures. The mode of action of tubulysin A resembled that of peptide antimitotics dolostatin 10, phomopsin A, and hemiasterlin. Efforts are underway to develop this new group of compounds as anticancer drugs.