Defining the biological roles of PRPS isozymes in normal and diseased settings

定义 PRPS 同工酶在正常和患病环境中的生物学作用

• 批准号: 10394225
• 负责人: Tom Cunningham
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394225
• 关键词: Affect; Bacteria; Biochemical; Biochemistry; Biological; Cells; Development; Disease; Economics; Enzymes; Foundations; Future; Genetic; Glean; Goals; Homeostasis; Human; Inborn Errors of Metabolism; Individual; Isoenzymes; Knowledge; Life; Malignant Neoplasms; Metabolic; Metabolism; Molecular; Mutation; Normal tissue morphology; Nucleotides; Phenotype; Physiological; Production; Property; Protein Isoforms; Regulation; Research; Ribose-Phosphate Pyrophosphokinase; Role; Structure; Work; cell behavior; clinically relevant; drug development; human disease; loss of function; man; mouse model; next generation; novel; nucleotide metabolism; programs; targeted treatment

PROJECT SUMMARY The phosphoribosyl pyrophosphate synthetase (PRPS) enzymes are critical regulators of nucleotide production in all life, from bacteria to man. These enzymes generate a critical precursor necessary for producing all nucleotide species and function as a `molecular throttle' capable of increasing or decreasing the rate at which these genetic building blocks are made. While targeting this metabolic enzyme represents a powerful approach to stymie nucleotide production, the redundancy afforded by the existence of two distinct forms of the same enzyme (PRPS1 and PRPS2) also presents a phenomenal opportunity for selectively treating certain diseases such as cancer. In order to realize this goal, however, we must first have a better understanding of their overlapping and distinct biological roles and the mechanistic basis for these similarities and differences. This proposal seeks to unravel the molecular basis for this selectivity through use of novel mouse models and elegant structure/function studies, thus pinpointing a putative mechanism of action and developing a rational basis for future drug development. We will focus our efforts on elucidating the distinct modes of regulation that control expression of the two separate isoforms as well as how the different biochemical properties of the individual isozymes regulate nucleotide production and metabolic homeostasis. To make our work clinically-relevant and applicable to human disease, we will also develop and characterize novel disease-specific mouse models of PRPS1 superactivity and loss of function that seek to recapitulate the mutations and phenotypes observed in human inborn errors of metabolism. Our research program ultimately strives to understand the complicated role of nucleotides in cellular metabolism and how their aberrant production, breakdown, transport, or utilization contributes to disease. For example, specifically within this proposal, we will elucidate the economics of nucleotide metabolism by determining how disrupting nucleotide supply affects the overall biochemistry of the cell. Collectively, the proposed studies and our research program in general will be transformative in our understanding of the roles of these key molecules in the normal and disease setting, and provide a new foundation for the development of the next generation of safer, more targeted therapies and rational approaches for ameliorating diseases associated with perturbed nucleotide homeostasis.

项目摘要 磷酸磷酸磷酸磷酸合成酶（PRPS）酶是核苷酸的关键调节剂 从细菌到人的所有生产中的生产。这些酶产生了必要的关键先驱 产生所有核苷酸物种，并充当能够增加或减少的“分子节气门” 这些遗传构建块的速率。在靶向这种代谢酶的同时代表 强大的阻塞核苷酸产生的方法，存在两个不同的冗余 同一酶的形式（PRPS1和PRPS2）也为有选择性的机会提供了一个惊人的机会 治疗某些疾病，例如癌症。但是，为了实现这一目标，我们必须首先要有更好的 了解它们的重叠和独特的生物学作用以及这些相似性的机理基础 和差异。该提议试图通过使用新颖的方法来揭示这种选择性的分子基础 小鼠模型和优雅的结构/功能研究，因此指出了推定的作用机理和 为未来的药物开发建立合理的基础。我们将集中精力阐明独特的 控制两个独立同工型的表达的调节模式以及如何不同 单个同工酶的生化特性调节核苷酸的产生和代谢稳态。 为了使我们的工作在临床上与人类疾病有关，我们还将发展和表征 新型疾病特异性的PRPS1超级活动和功能丧失的小鼠模型，试图概括 在人类天生的新陈代谢错误中观察到的突变和表型。我们的研究计划最终 努力了解核苷酸在细胞代谢中的复杂作用以及它们的异常 生产，分解，运输或利用会导致疾病。例如，特别是在此内 提案，我们将通过确定如何破坏核苷酸来阐明核苷酸代谢的经济学 供应会影响细胞的整体生物化学。拟议的研究和我们的研究计划总的来说 通常，我们对这些关键分子在正常和 疾病设置，并为下一代更安全的发展提供了新的基础 针对与扰动核苷酸相关的改善疾病的靶向疗法和合理方法 稳态。