Mechanism of Action of Tubulysin, an Antimitotic Peptide from Myxobacteria

Authors

  • Mohamed W. Khalil Dr.,

    1. Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany, Fax: (+49) 531-6181-395
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  • Florenz Sasse Dr.,

    1. Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany, Fax: (+49) 531-6181-395
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  • Heinrich Lünsdorf Dr.,

    1. Division of Microbiology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany
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  • Yasser A. Elnakady Dr.,

    1. Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany, Fax: (+49) 531-6181-395
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  • Hans Reichenbach Prof. Dr.

    1. Department of Natural Product Biology, GBF, German Research Center for Biotechnology, 38124 Braunschweig, Germany, Fax: (+49) 531-6181-395
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Abstract

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 G2/M phase. Tubulysin A inhibited tubulin polymerization more efficiently than vinblastine and induced depolymerization of isolated microtubule preparations. Microtubule depolymerization 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 apparent Ki was 3 μM. 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 dolastatin 10, phomopsin A, and hemiasterlin. Efforts are underway to develop this new group of compounds as anticancer drugs.

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