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: 10609812
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609812
• 关键词: Affect; Bacteria; Biochemical; Biochemistry; Biological; Cells; Development; Diphosphates; Disease; Economics; Enzymes; Foundations; Future; Genetic; Glean; Goals; Homeostasis; Human; Inborn Errors of Metabolism; Individual; Isoenzymes; Knowledge; Life; Ligase; Malignant Neoplasms; Metabolic; Metabolism; Molecular; Mutation; Normal tissue morphology; Nucleotides; Phenotype; Physiological; Production; Property; Protein Isoforms; Regulation; Research; Ribose-Phosphate Pyrophosphokinase; Role; Shapes; 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 磷酸核糖焦磷酸合成酶（PRPS）是核苷酸合成的关键调节剂， 从细菌到人类，所有生命都在生产。这些酶产生一种关键的前体， 产生所有的核苷酸种类，并作为能够增加或减少 这些基因构建模块的生成速率。虽然靶向这种代谢酶代表了一种 这是阻碍核苷酸生产的一种强有力的方法，两种不同的核苷酸存在所提供的冗余， 同样的酶（PRPS 1和PRPS 2）的形式也提供了一个惊人的机会， 治疗某些疾病，如癌症。然而，为了实现这一目标，我们必须首先有一个更好的 理解它们的重叠和不同的生物学作用以及这些相似性的机制基础 和差异。该建议试图通过使用新的分子生物学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，从而确定了一个假定的作用机制， 为未来的药物开发奠定了合理的基础。我们将集中精力阐明 控制两种不同亚型表达的调节模式以及不同亚型如何表达， 各个同工酶的生化特性调节核苷酸的产生和代谢稳态。 为了使我们的工作与临床相关并适用于人类疾病，我们还将开发和表征 PRPS 1超活性和功能丧失的新型疾病特异性小鼠模型试图概括 在人类先天性代谢缺陷中观察到的突变和表型。我们的研究计划最终 致力于了解核苷酸在细胞代谢中的复杂作用，以及它们的异常是如何发生的。 生产、分解、运输或利用都会导致疾病。具体来说，在这 建议，我们将阐明核苷酸代谢的经济学，通过确定如何破坏核苷酸 供应影响细胞的整体生物化学。总的来说，拟议的研究和我们的研究计划 在我们理解这些关键分子在正常和 疾病设置，并为下一代更安全，更安全的发展提供新的基础， 用于改善与干扰的核苷酸相关的疾病的靶向疗法和合理方法 体内平衡