QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 15, Issue 4, 1960-1968, April 2004

This Article Full Text Full Text (PDF) All Versions of this Article: E03-07-0530v1 15/4/1960    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morrissette, N. S. Articles by Sibley, L. D. Search for Related Content PubMed PubMed Citation Articles by Morrissette, N. S. Articles by Sibley, L. D.

Dinitroanilines Bind -Tubulin to Disrupt Microtubules

Naomi S. Morrissette ^* , Arpita Mitra  ^||, David Sept  ^||, and L. David Sibley ^*

^* Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Chemical Engineering, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri 63110; and ^|| Department of Center for Computational Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted July 25, 2003; Revised January 7, 2004; Accepted January 7, 2004
Monitoring Editor: Lawrence Goldstein

Protozoan parasites are remarkably sensitive to dinitroanilines such as oryzalin, which disrupt plant but not animal microtubules. To explore the basis of dinitroaniline action, we isolated 49 independent resistant Toxoplasma gondii lines after chemical mutagenesis. All 23 of the lines that we examined harbored single point mutations in -tubulin. These point mutations were sufficient to confer resistance when transfected into wild-type parasites. Several mutations were in the M or N loops, which coordinate protofilament interactions in the microtubule, but most of the mutations were in the core of -tubulin. Docking studies predict that oryzalin binds with an average affinity of 23 nM to a site located beneath the N loop of Toxoplasma -tubulin. This binding site included residues that were mutated in several resistant lines. Moreover, parallel analysis of Bos taurus -tubulin indicated that oryzalin did not interact with this site and had a significantly decreased, nonspecific affinity for vertebrate -tubulin. We propose that the dinitroanilines act through a novel mechanism, by disrupting M-N loop contacts. These compounds also represent the first class of drugs that act on -tubulin function.

Corresponding author and current address: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697. E-mail address: naomi{at}borcim.wustl.edu.

This article has been cited by other articles:

				A. Mitra and D. Sept Taxol Allosterically Alters the Dynamics of the Tubulin Dimer and Increases the Flexibility of Microtubules Biophys. J., October 1, 2008; 95(7): 3252 - 3258. [Abstract] [Full Text] [PDF]

				C. Ma, J. Tran, C. Li, L. Ganesan, D. Wood, and N. Morrissette Secondary Mutations Correct Fitness Defects in Toxoplasma gondii With Dinitroaniline Resistance Mutations Genetics, October 1, 2008; 180(2): 845 - 856. [Abstract] [Full Text] [PDF]

				D. Wloga, K. Rogowski, N. Sharma, J. Van Dijk, C. Janke, B. Edde, M.-H. Bre, N. Levilliers, V. Redeker, J. Duan, et al. Glutamylation on {alpha}-Tubulin Is Not Essential but Affects the Assembly and Functions of a Subset of Microtubules in Tetrahymena thermophila Eukaryot. Cell, August 1, 2008; 7(8): 1362 - 1372. [Abstract] [Full Text] [PDF]

				F. L. Henriquez, P. R. Ingram, S. P. Muench, D. W. Rice, and C. W. Roberts Molecular Basis for Resistance of Acanthamoeba Tubulins to All Major Classes of Antitubulin Compounds Antimicrob. Agents Chemother., March 1, 2008; 52(3): 1133 - 1135. [Abstract] [Full Text] [PDF]

				C. Ma, C. Li, L. Ganesan, J. Oak, S. Tsai, D. Sept, and N. S. Morrissette Mutations in {alpha}-Tubulin Confer Dinitroaniline Resistance at a Cost to Microtubule Function Mol. Biol. Cell, December 1, 2007; 18(12): 4711 - 4720. [Abstract] [Full Text] [PDF]

				K. Nagamune, S. N. J. Moreno, and L. D. Sibley Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis Antimicrob. Agents Chemother., November 1, 2007; 51(11): 3816 - 3823. [Abstract] [Full Text] [PDF]

				M. Cyrklaff, M. Kudryashev, A. Leis, K. Leonard, W. Baumeister, R. Menard, M. Meissner, and F. Frischknecht Cryoelectron tomography reveals periodic material at the inner side of subpellicular microtubules in apicomplexan parasites J. Exp. Med., June 11, 2007; 204(6): 1281 - 1287. [Abstract] [Full Text] [PDF]

				B. D. Dimitrov, P. G. Gadeva, D. K. Benova, and M. V. Bineva Comparative genotoxicity of the herbicides Roundup, Stomp and Reglone in plant and mammalian test systems Mutagenesis, November 1, 2006; 21(6): 375 - 382. [Abstract] [Full Text] [PDF]

				J. Ashby, E. Boutant, M. Seemanpillai, A. Sambade, C. Ritzenthaler, and M. Heinlein Tobacco mosaic virus movement protein functions as a structural microtubule-associated protein. J. Virol., September 1, 2006; 80(17): 8329 - 8344. [Abstract] [Full Text] [PDF]

				M. S. Miller, J. M. Esparza, A. M. Lippa, F. G. Lux III, D. G. Cole, and S. K. Dutcher Mutant Kinesin-2 Motor Subunits Increase Chromosome Loss Mol. Biol. Cell, August 1, 2005; 16(8): 3810 - 3820. [Abstract] [Full Text] [PDF]

				C. Delye, Y. Menchari, S. Michel, and H. Darmency Molecular Bases for Sensitivity to Tubulin-Binding Herbicides in Green Foxtail Plant Physiology, December 1, 2004; 136(4): 3920 - 3932. [Abstract] [Full Text] [PDF]

				M. Nakamura, K. Naoi, T. Shoji, and T. Hashimoto Low Concentrations of Propyzamide and Oryzalin Alter Microtubule Dynamics in Arabidopsis Epidermal Cells Plant Cell Physiol., September 15, 2004; 45(9): 1330 - 1334. [Abstract] [Full Text] [PDF]