Structure and Function of Metabolic Filaments

项目摘要 中间代谢必须精细调整，仔细平衡，并有力地适应环境的变化。 环境条件虽然驱动大多数代谢过程的单个酶都很好， 据了解，直到最近，该领域才开始认识到代谢酶自身的广泛作用， 在代谢组织和控制中的组装。特别是，我们现在知道， 在体内和体外组装成丝状结构，并且这些细丝充当变构效应物， 调节酶的活性。这项建议的重点是糖酵解和代谢酶的自组装丝， 核苷酸生物合成，从糖中提取能量并产生至关重要的 大分子结构单元。我们将使用低温电子显微镜来确定 组装和调节的基础，再加上生物化学，生物物理和细胞生物学方法， 理解代谢丝功能的综合方法。这项工作将提供深入了解具体的 聚合在调节酶功能中的作用，并阐明代谢控制的一般原理 通过酶丝。

PROJECT SUMMARY Intermediate metabolism must be finely tuned, carefully balanced, and robustly adaptable to changes in environmental conditions. While the individual enzymes that drive most metabolic processes are well understood, only recently has the field come to appreciate the widespread role of metabolic enzyme self- assembly in metabolic organization and control. In particular, we now know that dozens of metabolic enzymes assemble into filamentous structures in vivo and in vitro, and that these filaments act as allosteric effectors to tune enzyme activity. This proposal focuses on self-assembled filaments of metabolic enzymes in glycolysis and nucleotide biosynthesis, processes that extract energy from sugar and generate fundamentally important macromolecular building blocks, respectively. We will use cryo-electron microscopy to determine the structural basis for assembly and regulation, coupled with biochemical, biophysical, and cell biological approaches in an integrative approach to understanding metabolic filament function. This work will provide insight into the specific roles polymerization plays in modulating enzyme function, and illuminate general principles of metabolic control by enzyme filaments.