Rid family members neutralize endogenous metabolic stressors

Rid 家族成员中和内源性代谢应激源

基本信息

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
项目类别：
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

项目摘要

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.

概括生命系统的一个基本特征是其集成的生化途径网络，该网络响应内源性压力以及环境施加的压力。微生物，特别是那些具有良好发达的遗传系统，为表征应激反应提供了独特的机会进化为控制代谢过程产生的反应性代谢物。代谢策略是保守的跨生物学，从微生物系统获得的见解提供了增进我们理解的方法一般代谢范式。 PI 研究的长期目标是了解稳健性和代谢网络的冗余，并定义代谢成分及其参与的过程 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、治疗代谢疾病的努力以及针对新陈代谢的努力例如，合理的药物设计和/或有价值化学品的生产。本文提出的工作目标是表征由反应性导致的代谢应激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。这研究重点是高度保守的 Rid 蛋白家族及其创始细菌成员 RidA。在目前的提案我们将： i) 进一步了解 RidA 和其他家族使用的机制成员消除内源性烯胺/亚胺应激； ii) 描述额外的、独特的已经发展出应对类似压力的机制； iii) 探讨这种压力的广度以及如何不同的生物体可以处理它。该提案的目标将通过以下方面的结合来实现：化学、生物化学、生物物理、分子、遗传和生物信息学方法。这里的工作是出于我们想要了解反应性代谢物产生所产生的代谢应激的愿望在生长过程中，以及如果不被中和，它会如何损害细胞成分。