Abstract.
Several marine macrolide toxins act as potent and specific actin-severing molecules. Recent elucidation of their stereochemistries and modes of interaction with actin has allowed the syntheses of bioactive analogues. Here we used synthetic analogues in a structure-function analysis of ulapualide A, a trisoxazole-based macrolide. Ulapualide A harboured potent actin-depolymerising activity both in cells and in vitro. Its synthetic diastereoisomer was three orders of magnitude less active than the natural toxin and synthetic macrolide fragments lacked actin-capping/ severing activity altogether. Modulation of serum response factor (SRF)-dependent gene expression, as described for other actin-binding toxins, was also examined. Specific changes in response to ulapualide A were not observed, primarily due to its profound effects on cytoskeletal integrity and cell adhesion. Several synthetic fragments of ulapualide A also had no effect on SRF-dependent gene expression. However, inhibition was observed with a molecule corresponding to the extended aliphatic side chain of halichondramide, a structurally related macrolide. These findings indicate that side-chain derivatives of trisoxazole-based macrolides may serve to uncouple gene-regulatory events from actin dynamics.
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E. Vincent and J. Saxton: These two authors contributed equally
Received 27 September 2006; received after revision 30 November 2006; accepted 8 January 2007
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Vincent, E., Saxton, J., Baker-Glenn, C. et al. Effects of ulapualide A and synthetic macrolide analogues on actin dynamics and gene regulation. Cell. Mol. Life Sci. 64, 487 (2007). https://doi.org/10.1007/s00018-007-6427-1
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DOI: https://doi.org/10.1007/s00018-007-6427-1