Contrasting effects of maytansine and vinblastine on the alkylation of tubulin sulfhydryls

Richard F. Luduena, Mary Carmen Roach

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

The ansa macrolide maytansine is a competitive inhibitor of vinblastine for binding to tubulin. Both drugs are potent inhibitors of microtubule assembly in vitro but maytansine, unlike vinblastine, is unable to induce tubulin aggregation or to stabilize colchicine binding. In this study, the effects of maytansine and vinblastine on the accessibility of tubulin's sulfhydryl groups were compared. It was found that 10 μm vinblastine inhibited the reaction of bovine brain tubulin with [14C]iodoacetamide by 45%. In contrast, maytansine, even up to 100 μm, had no effect on the reaction. However, when the two drugs were tested in combination, maytansine was a potent inhibitor of vinblastine's effect, consistent with the two drugs competing for the same or overlapping sites, but suggesting that the nature of the binding was different. In contrast, maytansine did not affect the suppression of alkylation induced by colchicine and podophylotoxin, consistent with these drugs binding to different sites. Maytansine and vinblastine were each able to increase the formation of β* by the bifunctional reagent, N,N′-ethylenebis-(iodoacetamide); β* is the designation for an electrophoretically faster migrating form of β-tubulin which apparently contains an intrachain crosslink. Thus, in at least the portion of the tubulin molecule involved in β* formation, the two drugs have similar effects. Since maytansine does not appear to suppress any competing alkylation reactions, it is possible that the enhancement of β* formation represents a genuine conformational effect. Since the sulfhydryl groups of tubulin may be involved in regulating microtubule assembly, it is likely that maytansine and vinblastine differ in the manner in which they inhibit microtubule assembly.

Original languageEnglish (US)
Pages (from-to)498-504
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume210
Issue number2
DOIs
StatePublished - Sep 1981

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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