The Structure and Function of Metabolic Filaments

 描述（由申请人提供）：核糖核苷酸是对几乎所有细胞过程都至关重要的小分子。它们是DNA和RNA的组成部分，是细胞代谢的重要前体和中间体，提供能量以驱动细胞过程，并在调节细胞活性方面发挥重要作用。由于其核心重要性，新的核糖核苷酸的生产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平衡的一种方式是调节两种至关重要的酶CTPS和IMPDH的活性。由于它们在调节核糖核苷酸丰度和平衡中的关键作用，CTPS和IMPDH是化疗和抗寄生虫应用的重要药物靶标，并且IMPDH与导致失明的人类疾病有关。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，这些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，改变了我们对代谢酶调节的看法，并为靶向药物设计开辟了新的可能性。该提案旨在在分子水平上了解CTPS和IMPDH如何组装成大规模结构，这些结构如何影响酶的活性，以及细胞如何操纵这些结构以保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.