Epothilone and Paclitaxel: Unexpected Differences in Promoting the Assembly and Stabilization of Yeast Microtubules

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• 作者：Claudia J. Bode ; Mohan L. Gupta ; Jr. ; Emily A. Reiff ; Kathy A. Suprenant ; Gunda I. Georg ; and Richard H. Himes
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：March 26, 2002
• 年：2002
• 卷：41
• 期：12
• 页码：3870 - 3874
• 全文大小：95K
• 年卷期：v.41,no.12(March 26, 2002)
• ISSN：1520-4995

文摘

Paclitaxel (Taxol) and the epothilones are antimitotic agents that promote the assembly ofmammalian tubulin and stabilization of microtubules. The epothilones competitively inhibit the bindingof paclitaxel to mammalian brain tubulin, suggesting that the two types of compounds share a commonbinding site in tubulin, despite the lack of structural similarities. It is known that paclitaxel does notstabilize microtubules formed in vitro from Saccharomyces cerevisiae tubulin; thus, it would be expectedthat the epothilones would not affect yeast microtubules. However, we found that epothilone A and B dostimulate the formation of microtubules from purified yeast tubulin. In addition, epothilone B severelydampens the dynamics of yeast microtubules in vitro in a manner similar to the effect of paclitaxel onmammalian microtubules. We used current models describing paclitaxel and epothilone binding tomammalian ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-tubulin to explain why paclitaxel apparently fails to bind to yeast tubulin. We propose thatthree amino acid substitutions in the N-terminal region and at position 227 in yeast ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-tubulin weaken theinteraction of the 3'-benzamido group of paclitaxel with the protein. These results also indicate thatmutagenesis of yeast tubulin could help define the sites of interaction with paclitaxel and the epothilones.