Effects of ulapualide A and synthetic macrolide analogues on actin dynamics and gene regulation.
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.
Vincent
E
E
Centre for Biochemistry and Cell Biology, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
Saxton
J
J
Baker-Glenn
C
C
Moal
I
I
Hirst
J D
JD
Pattenden
G
G
Shaw
P E
PE
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; D018942:Macrolides; D010080:Oxazoles; C085516:ulapualide A; C470372:halichondramide