Caulerpenyne Binding to Tubulin: Structural Modifications by a Non Conventional Pharmacological Agent

Julien      Bourdron; Pascale      Barbier; Diane      Allegro; Claude      Villard; Daniel      Lafitte; Laurent      Commeiras; Jean-Luc      Parrain; Vincent      Peyrot

doi:10.2174/157340609787582891

Abstract

The most widely used molecules in cancer chemotherapy are Vinca-alkaloids and Taxoids, numerous chemists attempted the synthesis of analogs which bind to their well-known tubulin pharmacological site. Unfortunately, tumors develop resistance to these compounds; therefore the definition of anchoring points and potential binding sites for new drugs on tubulin is of major interest. Caulerpenyne (Cyn), the major secondary metabolite synthesized by the green marine alga Caulerpa taxifolia could be one of these drugs, since it inhibits the assembly of tubulin and MTP (Barbier et al., 2001). We observed that the tubulin-Cyn complex is poorly reversed. Cyn did not bind to sulfhydryl groups and the measure of the extent of binding is 1.6 ± 0.2 suggesting two potential binding sites. Then, we demonstrated by competition measurements that Cyn did not interact to colchicine, Taxol® and Vinca-alkaloid binding domain. Finally, mass spectrometric analysis of proteolytic cleavage of tubulin-Cyn complex demonstrated that Cyn did not bind covalently to tubulin and evidenced two good candidate regions for Cyn binding, one on α-tubulin and the other on β-tubulin.

Keywords: Tubulin, caulerpenyne, MALDI-TOF, microtubule, electrospray

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