Mechanism of interaction of vinca alkaloids with tubulin: catharanthine and vindoline.
The interactions of the vinca alkaloid drugs catharanthine and vindoline with tubulin have been investigated and compared with those of vinblastine and vincristine. Both drugs were found to be less effective in bringing about the inhibition of tubulin self-assembly into microtubules than vincristine and vinblastine, the drug to protein molar ratio required being 3 orders of magnitude greater. An analytical ultracentrifuge study has shown that catharanthine can induce the self-association of tubulin into linear indefinite polymers with an efficacy that is 75% that of vinblastine or vincristine, the intrinsic dimerization constant for the liganded protein being K2 congruent to 1 x 10(5) M-1. The effect of vindoline was marginally detectable. Binding studies of catharanthine using the gel batch and fluorescence perturbation techniques showed a polymerization-linked binding of one catharanthine molecule per tubulin alpha-beta dimer with a binding constant of (2.8 +/- 0.4) x 10(3) M-1. For vindoline, binding to tubulin was marginally detectable by fluorescence spectroscopy, although addition of vindoline to tubulin did generate a difference spectrum. It was concluded that the binding of vinblastine/vincristine to tubulin and its consequences are determined by the interaction of the indole part of catharanthine with tubulin, the role of vindoline being that of an anchor.
Prakash
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Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254-9110.
Timasheff
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D000818:Animals; D001923:Brain Chemistry; D002417:Cattle; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D014404:Tubulin / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014748:Vinca Alkaloids / Q000493:pharmacokinetics*
D014404:Tubulin; D014748:Vinca Alkaloids; C009667:vindoline; D014747:Vinblastine; C017836:catharanthine