Phosphinic Acid-based Inhibitors of Tubulin Polyglutamylases

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2013 Jun 20

PMID 23777780

Citations 5

Authors

Yanjie Liu

Christopher P Garnham

Antonina Roll-Mecak

Martin E Tanner

Affiliations

Soon will be listed here.

Abstract

Tubulin is subject to a reversible post-translational modification involving polyglutamylation and deglutamylation of glutamate residues in its C-terminal tail. This process plays key roles in regulating the function of microtubule associated proteins, neuronal development, and metastatic progression. This study describes the synthesis and testing of three phosphinic acid-based inhibitors that have been designed to inhibit both the glutamylating and deglutamylating enzymes. The compounds were tested against the polyglutamylase TTLL7 using tail peptides as substrates (100 μM) and the most potent inhibitor displayed an IC₅₀ value of 150 μM. The incorporation of these compounds into tubulin C-terminal tail peptides may lead to more potent TTLL inhibitors.

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References

Valiaeva N, Bartley D, Konno T, Coward J . Phosphinic acid pseudopeptides analogous to glutamyl-gamma-glutamate: synthesis and coupling to pteroyl azides leads to potent inhibitors of folylpoly-gamma-glutamate synthetase. J Org Chem. 2001; 66(15):5146-54. DOI: 10.1021/jo010283t. View

Jinushi-Nakao S, Arvind R, Amikura R, Kinameri E, Liu A, Moore A . Knot/Collier and cut control different aspects of dendrite cytoskeleton and synergize to define final arbor shape. Neuron. 2007; 56(6):963-78. DOI: 10.1016/j.neuron.2007.10.031. View

Ikegami K, Heier R, Taruishi M, Takagi H, Mukai M, Shimma S . Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function. Proc Natl Acad Sci U S A. 2007; 104(9):3213-8. PMC: 1802010. DOI: 10.1073/pnas.0611547104. View

Suryavanshi S, Edde B, Fox L, Guerrero S, Hard R, Hennessey T . Tubulin glutamylation regulates ciliary motility by altering inner dynein arm activity. Curr Biol. 2010; 20(5):435-40. PMC: 2910546. DOI: 10.1016/j.cub.2009.12.062. View

Wade R . On and around microtubules: an overview. Mol Biotechnol. 2009; 43(2):177-91. DOI: 10.1007/s12033-009-9193-5. View

Rogowski K, van Dijk J, Magiera M, Bosc C, Deloulme J, Bosson A . A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell. 2010; 143(4):564-78. DOI: 10.1016/j.cell.2010.10.014. View

Roll-Mecak A, McNally F . Microtubule-severing enzymes. Curr Opin Cell Biol. 2009; 22(1):96-103. PMC: 2822099. DOI: 10.1016/j.ceb.2009.11.001. View

Dive V, Georgiadis D, Matziari M, Makaritis A, Beau F, Cuniasse P . Phosphinic peptides as zinc metalloproteinase inhibitors. Cell Mol Life Sci. 2004; 61(16):2010-9. PMC: 11138626. DOI: 10.1007/s00018-004-4050-y. View

Kimura Y, Kurabe N, Ikegami K, Tsutsumi K, Konishi Y, Kaplan O . Identification of tubulin deglutamylase among Caenorhabditis elegans and mammalian cytosolic carboxypeptidases (CCPs). J Biol Chem. 2010; 285(30):22936-41. PMC: 2906286. DOI: 10.1074/jbc.C110.128280. View

10.

Lacroix B, van Dijk J, Gold N, Guizetti J, Aldrian-Herrada G, Rogowski K . Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. J Cell Biol. 2010; 189(6):945-54. PMC: 2886356. DOI: 10.1083/jcb.201001024. View

11.

Janke C, Bulinski J . Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011; 12(12):773-86. DOI: 10.1038/nrm3227. View

12.

Ikegami K, Mukai M, Tsuchida J, Heier R, MacGregor G, Setou M . TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. J Biol Chem. 2006; 281(41):30707-16. PMC: 3049811. DOI: 10.1074/jbc.M603984200. View

13.

Redeker V, Rusconi F, Mary J, Prome D, Rossier J . Structure of the C-terminal tail of alpha-tubulin: increase of heterogeneity from newborn to adult. J Neurochem. 1996; 67(5):2104-14. DOI: 10.1046/j.1471-4159.1996.67052104.x. View

14.

Tanner M, Vaganay S, van Heijenoort J, Blanot D . Phosphinate Inhibitors of the D-Glutamic Acid-Adding Enzyme of Peptidoglycan Biosynthesis. J Org Chem. 1996; 61(5):1756-1760. DOI: 10.1021/jo951780a. View

15.

Barinka C, Hlouchova K, Rovenska M, Majer P, Dauter M, Hin N . Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs. J Mol Biol. 2008; 376(5):1438-50. PMC: 2753231. DOI: 10.1016/j.jmb.2007.12.066. View

16.

Soucek K, Kamaid A, Phung A, Kubala L, Bulinski J, Harper R . Normal and prostate cancer cells display distinct molecular profiles of alpha-tubulin posttranslational modifications. Prostate. 2006; 66(9):954-65. DOI: 10.1002/pros.20416. View

17.

van Dijk J, Rogowski K, Miro J, Lacroix B, Edde B, Janke C . A targeted multienzyme mechanism for selective microtubule polyglutamylation. Mol Cell. 2007; 26(3):437-48. DOI: 10.1016/j.molcel.2007.04.012. View

18.

Yiotakis A, Vassiliou S, Jiracek J, Dive V . Protection of the Hydroxyphosphinyl Function of Phosphinic Dipeptides by Adamantyl. Application to the Solid-Phase Synthesis of Phosphinic Peptides. J Org Chem. 1996; 61(19):6601-6605. DOI: 10.1021/jo9603439. View

19.

Garnham C, Roll-Mecak A . The chemical complexity of cellular microtubules: tubulin post-translational modification enzymes and their roles in tuning microtubule functions. Cytoskeleton (Hoboken). 2012; 69(7):442-63. PMC: 3459347. DOI: 10.1002/cm.21027. View

20.

Zhang D, Rogers G, Buster D, Sharp D . Three microtubule severing enzymes contribute to the "Pacman-flux" machinery that moves chromosomes. J Cell Biol. 2007; 177(2):231-42. PMC: 2064132. DOI: 10.1083/jcb.200612011. View