Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z1.
Bioorg Med Chem Lett. 2013 Aug 1;23(15):4408-12. doi: 10.1016/j.bmcl.2013.05.069. Epub 2013 May 30.
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.
微管蛋白会发生涉及谷氨酸残基在其 C 末端尾部的多聚谷氨酸化和去谷氨酸化的可逆翻译后修饰。这个过程在调节微管相关蛋白的功能、神经元发育和转移进展方面起着关键作用。本研究描述了三种基于膦酸的抑制剂的合成和测试，这些抑制剂旨在抑制谷氨酰化酶和去谷氨酰化酶。这些化合物在尾巴肽作为底物的情况下（100 μM）针对多聚谷氨酸酶 TTLL7 进行了测试，最有效的抑制剂显示出的 IC₅₀ 值为 150 μM。将这些化合物掺入微管蛋白 C 末端尾部肽中可能会导致更有效的 TTLL 抑制剂。
