Effects of ulapualide A and synthetic macrolide analogues on actin dynamics and gene regulation |
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Authors: | E Vincent J Saxton C Baker-Glenn I Moal J D Hirst G Pattenden P E Shaw |
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Institution: | (1) Centre for Biochemistry and Cell Biology, School of Biomedical Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH, UK;(2) School of Chemistry, University Park, Nottingham, NG7 2RD, UK;(3) Present address: Department of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK |
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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.
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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