Isolation, Crystal and Solution Structure Determination, and Biosynthesis of Tubulysins—Powerful Inhibitors of Tubulin Polymerization from Myxobacteria

Authors

  • Heinrich Steinmetz Ing.,

    1. Bereich Naturstoffe, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, Fax: (+49) 531-6181461
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  • Nicole Glaser Dr.,

    1. Bereich Naturstoffe, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, Fax: (+49) 531-6181461
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  • Eberhardt Herdtweck Dr.,

    1. Institut für Anorganische Chemie, Technische Universität München, München, Germany
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  • Florenz Sasse Dr.,

    1. Bereich Naturstoffe, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, Fax: (+49) 531-6181461
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  • Hans Reichenbach,

    1. Bereich Naturstoffe, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, Fax: (+49) 531-6181461
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  • Gerhard Höfle Prof. Dr.

    1. Bereich Naturstoffe, Gesellschaft für Biotechnologische Forschung mbH, Mascheroder Weg 1, 38124 Braunschweig, Germany, Fax: (+49) 531-6181461
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  • Antibiotics from Gliding Bacteria, Part 100; for Part 99, see: B. Kunze, R. Jansen, G. Höfle, H. Reichenbach, J. Antibiot.2004, 57, 151–155. We thank I. Schleicher, K. Schober, S. Reinecke, A. Ritter, and B. Hinkelmann for technical assistance, Dr. A. Ross and colleagues at the bio-pilotplant of the GBF for help with fermentations, Dr. V. Wray and colleagues for recording NMR and mass spectra, and Dr. H.-J. Hecht for generating stereopictures. We also thank Prof. G. R. Pettit for a generous gift of dolastatin 10. This work was supported by Morphochem AG and the Fonds der Chemischen Industrie.

Abstract

original image

Myxobacteria have it both ways: Whereas the epothilones stabilize the tubulin cytoskeleton and build microtubuli, tubulysins, which have now been isolated from Archangium gephyra and Angiococcus disciformis, have exactly the opposite effect. They induce the disintegration of the microtubuli, and even picomolar concentrations can cause cell death by apoptosis. Their effect on cell cultures exceeds that of the most active epothilones by 50-fold.

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