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腾讯登录Nat Commun：新型蛋白质图谱或可帮助寻找潜在的抗癌药物
| 导读 | 近日，一项发表在国际杂志Nature Communications上的研究报告中，来自伦敦帝国理工学院的研究人员通过研究揭示了致病性酶类如何对蛋白质进行修饰及其如何被阻断的分子机制；这种酶类名为N-肉豆蔻酰基转移酶(NMT)，研究人员希望该研究可以帮助他们设计新型药物来靶向作用该酶类，为癌症及炎性疾病开发新型靶向性疗法。 |
近日，一项发表在国际杂志Nature Communications上的研究报告中，来自伦敦帝国理工学院的研究人员通过研究揭示了致病性酶类如何对蛋白质进行修饰及其如何被阻断的分子机制；这种酶类名为N-肉豆蔻酰基转移酶(NMT)，研究人员希望该研究可以帮助他们设计新型药物来靶向作用该酶类，为癌症及炎性疾病开发新型靶向性疗法。
文章中，研究者鉴别出了一种可以阻断NMT活性的分子，并且发现了该分子具有潜在效应的特殊蛋白底物；NMT可以引发蛋白质不可逆的改变，而且其参与了一系列疾病的发生，比如癌症、癫痫症和阿尔兹海默氏症等。本文研究中，研究人员利用人类活性肿瘤细胞进行研究鉴别出了被NMT修饰的100多个蛋白质，几乎所有的蛋白质都是首次在自然环境中被鉴别发现。随后研究人员对所有的蛋白质进行绘图，并且确定了可以阻断NMT活性的小分子；Ed Tate教授表示，目前我们已经揭示了NMT的工作机理，更重要的是我们找到了抑制其活性的途径，这在之前研究中是不可能的。文章中我们绘制的蛋白质图谱可以帮助我们理解如何去抑制NMT的效应，这就意味着我们可以通过靶向作用NMT来开发抵御疾病的新型疗法。
下一步研究者利用质谱技术对NMT抑制分子的效应进行了定量，研究人员通过诱导细胞凋亡，即让细胞发生程序性死亡来检测抑制分子和NMT之间的相互作用；细胞凋亡对于癌症化疗至关重要，而且其在药物耐受性的癌症中经常会失活。目前研究人员发现NMT可以在细胞凋亡期间修饰一系列蛋白，但是研究者可以鉴别出许多受NMT影响的新型蛋白，这就为开发抵御耐药性癌症的疗法提供了新的思路。
目前研究人员正在寻找一种可以潜在阻断NMT修饰蛋白质能力的药物分子，本文研究则为早日找到这种新型的药物分子提供了一定帮助，研究人员希望在未来5至10年内将本文的研究成果应用到临床中去，早日开发出治疗癌症等一系列疾病的靶向性疗法。（转化医学网360zhyx.com）
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Global profiling of co- and post-translationally N-myristoylated proteomes in human cells
Nature Communications doi:10.1038/ncomms5919
Emmanuelle Thinon, Remigiusz A. Serwa, Malgorzata Broncel, James A. Brannigan, Ute Brassat, Megan H. Wright, William P. Heal, Anthony J. Wilkinson, David J. Mann & Edward W. Tate
Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in the development and progression of a range of human diseases. Here, we report the global N-myristoylated proteome in human cells determined using quantitative chemical proteomics combined with potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of N-myristoylation during normal growth or apoptosis allowed the identification of >100 N-myristoylated proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.
Nature Communications doi:10.1038/ncomms5919
Emmanuelle Thinon, Remigiusz A. Serwa, Malgorzata Broncel, James A. Brannigan, Ute Brassat, Megan H. Wright, William P. Heal, Anthony J. Wilkinson, David J. Mann & Edward W. Tate
Protein N-myristoylation is a ubiquitous co- and post-translational modification that has been implicated in the development and progression of a range of human diseases. Here, we report the global N-myristoylated proteome in human cells determined using quantitative chemical proteomics combined with potent and specific human N-myristoyltransferase (NMT) inhibition. Global quantification of N-myristoylation during normal growth or apoptosis allowed the identification of >100 N-myristoylated proteins, >95% of which are identified for the first time at endogenous levels. Furthermore, quantitative dose response for inhibition of N-myristoylation is determined for >70 substrates simultaneously across the proteome. Small-molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.
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