The active GTP- and ground GDP-liganded states of tubulin are distinguished by the binding of chiral isomers of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate

Biochemistry
Pascale BarbierJosé Manuel Andreu

Abstract

NSC 613862 (S)-(-) and NSC 613863 (R)-(+) are the two chiral isomers of ethyl-5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3, 4-b]pyrazin-7-yl carbamate. Both compounds bind to tubulin in a region that overlaps the colchicine site. They induce formation of abnormal polymers from purified GTP-Mg-tubulin, the active assembly form of tubulin, in glycerol-free buffer with magnesium [De Ines, C., Leynadier, D., Barasoain, I., Peyrot, V., Garcia, P., Briand, C., Rener, G. A., and Temple, C., Jr. (1994) Cancer Res. 54, 75-84]. In this study, we observed that the S-isomer can promote polymerization of GDP-tubulin, the inactive assembly-incompetent form of tubulin, into nonmicrotubular structures at a critical protein concentration of 1 mg/mL (12 mM MgCl2). Neither the R-isomer nor colchicine have this ability. By electron microscopy, these tubulin polymers showed the same poorly defined filamentous structure when GDP-tubulin or GTP-Mg-tubulin were used. By HPLC measurements, we demonstrated that a dissociated GTP hydrolysis and exchange of nucleotide occurred during the isomer-induced abnormal assembly. Both isomers inhibited the Mg2+-induced tubulin self-association leading to 42 S double ring formation from GTP-Mg-tubulin or GDP-tubul...Continue Reading

References

Feb 1, 1991·Current Opinion in Cell Biology·M F Carlier
Nov 5, 1974·Journal of Molecular Biology·M JacobsE W Taylor

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Citations

Mar 17, 2001·International Journal of Biological Macromolecules·A A Tulub, V E Stefanov
Jan 23, 1999·Current Opinion in Structural Biology·K H Downing, E Nogales
Aug 3, 2010·The Journal of Biological Chemistry·Pascale BarbierJose M Andreu
Apr 7, 2011·The Journal of Biological Chemistry·Antonio J Martin-GalianoJose M Andreu
Sep 10, 2014·International Journal of Molecular Sciences·Isabelle L Di MaïoVincent Peyrot
Apr 30, 2014·Journal of Medicinal Chemistry·María-Dolores CanelaEva-María Priego
Dec 17, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Laziza AmniaiIsabelle Landrieu
May 31, 2003·The Journal of Biological Chemistry·Emmanuelle LaurineJean-Michel Verdier
Jan 7, 2000·Journal of Molecular Biology·C SmyczynskiP Chaussepied

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