Rid family members neutralize endogenous metabolic stressors

摘要 生命系统的一个基本特征是其由生物化学途径组成的综合网络，这些生物化学途径对 内源压力以及环境施加的压力。微生物，特别是那些有井的微生物- 发达的遗传系统，为表征具有 进化以控制代谢过程中产生的反应性代谢物。新陈代谢策略是保守的 通过生物学，从微生物系统获得的见解提供了促进我们理解的手段 一般新陈代谢模式。PI研究的长期目标是了解健壮性和 代谢网络的冗余性，并定义代谢成分及其参与的过程 在……里面。对新陈代谢过程的严格理解对于预测细胞如何反应至关重要 环境变化，旨在治疗代谢性疾病的努力，以及针对新陈代谢的努力 对于合理的药物设计和/或生产有价值的化学品，仅举几例。 本文提出的工作目标是描述由反应性引起的代谢应激的特征。 在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，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 消除内源性烯胺/亚胺应激的成员；ii)描述额外的、不同的 进化为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。这项提案的目标将通过以下方式相结合来实现 化学、生化、生物物理、分子、遗传和生物信息学方法。这里的工作是 受我们渴望了解由产生反应性代谢物产生的代谢压力的激励 在生长过程中，以及如果不中和它会如何破坏细胞成分。

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.