The Structure and Function of Metabolic Filaments

 描述(申请人提供)：核糖核苷酸是对几乎所有细胞过程至关重要的小分子。它们是DNA和RNA的构件，是细胞代谢的重要前体和中间体，为推动细胞过程提供能量，并在调节细胞活动中发挥重要作用。由于它们的核心重要性，新的核糖核苷酸的产生在细胞中受到非常严格的控制。细胞控制核糖核苷酸数量和不同类型核苷酸之间的平衡的一种方法是调节两种至关重要的酶--CTPS和IMPDH的活性。由于CTPS和IMPDH在调节核糖核苷酸丰度和平衡方面起着关键作用，它们是化疗和抗寄生虫应用的重要药物靶点，IMPDH与人类导致失明的疾病有关。虽然CTPS和IMPDH已经被详细研究了几十年，但我们直到最近才了解到，这两种酶共同组装成大规模结构，对维持细胞中的代谢平衡至关重要。这一发现创造了新的研究领域，正在改变我们对代谢酶调节的思考方式，并为靶向药物设计开辟了新的可能性。这一建议旨在从分子水平上了解CTPS和IMPDH是如何组装成大规模结构的，这些结构是如何影响酶的活性的，以及细胞如何操纵这些结构来维持最佳的核糖核苷酸水平。

 DESCRIPTION (provided by applicant): Ribonucleotides are small molecules that are fundamentally important to almost all cellular processes. They are the building blocks of DNA and RNA, are important precursors and intermediates in cellular metabolism, provide energy to drive cellular processes, and play important roles in regulating cellular activity. Because of thei central importance the production of new ribonucleotides is very tightly controlled in cells. One way the cell controls both the number of ribonucleotides and the balance between different types of nucleotides is to modulate the activity of two critically important enzymes, CTPS and IMPDH. Because of their critical roles in regulating ribonucleotide abundance and balance, CTPS and IMPDH are important drug targets for both chemotherapy and anti-parasitic applications, and IMPDH is implicated in human diseases that lead to blindness. While CTPS and IMPDH have been studied in detail for decades we only very recently learned that the enzymes co-assemble into large-scale structures that are important in maintaining metabolic balance in the cell. This discovery has created new areas of research that are changing the way we think about the regulation of metabolic enzymes and has opened up new possibilities for targeted drug design. This proposal aims to understand at the molecular level how CTPS and IMPDH assemble into large-scale structures, how these structures influence the activity of the enzymes, and how the celll manipulates these structures to maintain optimal ribonucleotide levels.