Rid family members neutralize endogenous metabolic stressors

Rid 家族成员中和内源性代谢应激源

• 批准号: 9323487
• 负责人: Diana M. Downs
• 金额: $ 29.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323487
• 关键词: Active Sites; Address; Bacteria; Bacterial Model; Behavior; Biochemical; Biochemical Pathway; Bioinformatics; Biological Assay; Biological Models; Biology; Biophysics; Catalysis; Cell Survival; Cell physiology; Cells; Chemicals; Cytosol; Deaminase; Diffuse; Drug Design; Environment; Enzymes; Family; Family member; Funding; Genetic; Goals; Grant; Growth; Hydrolysis; Imines; In Vitro; Laboratories; Life; Lyase; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methanococcus; Microbe; Molecular Genetics; Names; Organism; Pathway Analysis; Physiological; Process; Production; Protein Family; Reproducibility; Research; Role; Salmonella enterica; Solvents; Stress; System; Variant; Water; Work; biological adaptation to stress; biological systems; cellular targeting; environmental change; enzyme mechanism; gene product; genetic analysis; in vivo; insight; man; member; microbial; mutant; response; small molecule; stressor

SUMMARY A fundamental feature of a living system is its integrated network of biochemical pathways that respond to endogenous stresses as well as those applied by the environment. Microbes, particularly those with a well- developed genetic system, provide a unique opportunity for the characterization of stress responses that have evolved to control reactive metabolites generated by metabolic processes. Metabolic strategies are conserved across biology, and insights obtained from microbial systems provide the means to advance our understanding of general metabolic paradigms. The long-term goal of the PI's research is to understand the robustness and redundancy of the metabolic network, and to define metabolic components and the processes they participate in. A rigorous understanding of metabolic processes is critical to efforts aimed at predicting how cells respond to environmental change, to efforts aimed at treating metabolic diseases, and to efforts targeting metabolism for rational drug design and/or production of value chemicals, to name a few. The goal of the work proposed herein is to characterize a metabolic stress that results form reactive metabolites generated during growth and to understand the family of proteins that neutralize this stress. This study focuses on the highly conserved Rid protein family, and the founding bacterial member RidA. In the current proposal we will: i) further our understanding of the mechanism used by RidA and other family members to eliminate endogeneously generated enamine/imine stress; ii) describe additional, distinct mechanisms that have evolved to deal with similar stress; and iii) explore the breadth of this stress and how different organisms handle it. The goals of this proposal will be accomplished through the combination of chemical, biochemical, biophysical, molecular, genetic and bioinformatics approaches. The work here is motivated by our desire to understand the metabolic stress generated by the production of reactive metabolites during growth, and how it can damage cellular components if it is not neutralized.

总结 生命系统的一个基本特征是其生物化学途径的集成网络， 内源性压力以及环境施加的压力。微生物，特别是那些有良好- 发达的遗传系统，提供了一个独特的机会，表征压力反应， 进化来控制代谢过程产生的活性代谢物。代谢策略是保守的 从微生物系统中获得的见解提供了促进我们理解的手段 一般的新陈代谢模式。PI研究的长期目标是了解 代谢网络的冗余，并定义代谢组件及其参与的过程 in.对代谢过程的严格理解对于旨在预测细胞如何反应的努力至关重要 环境变化，旨在治疗代谢性疾病的努力，以及针对代谢的努力 用于合理的药物设计和/或有价值的化学品的生产，仅举几例。 本文提出的工作的目标是表征代谢应激，其结果是反应性的， 研究生长过程中产生的代谢物，并了解中和这种压力的蛋白质家族。这 这项研究的重点是高度保守的Rid蛋白家族，以及细菌的创始成员RidA。在 目前的建议，我们将：i）进一步了解RidA和其他家庭使用的机制 成员以消除内源性产生的烯胺/亚胺应激; ii）描述另外的、不同的 已经发展到处理类似压力的机制;以及iii）探索这种压力的广度以及如何 不同的生物体处理它。本提案的目标将通过结合 化学、生物化学、生物物理、分子、遗传和生物信息学方法。这里的工作 我们希望了解由活性代谢物产生的代谢应激， 在生长过程中，以及如果不中和，它如何损害细胞成分。