Rid family members neutralize endogenous metabolic stressors

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， 内源性和环境压力。在人类中，新陈代谢网络 功能障碍和疾病。代谢策略在生物学中是保守的，从模型中获得的见解 生物体提供的手段，以促进我们的一般代谢模式的理解，这往往可以 可以外推到包括人类在内的高等生物。PI研究的长期目标是 了解代谢网络的鲁棒性和冗余性，并定义代谢组件， 他们参与的过程。代谢过程的知识和机械的理解， 未知蛋白质的功能对于旨在治疗代谢性疾病的努力以及靶向 用于合理药物设计的代谢、合成生物学、微生物组研究等。 本文所提出的工作的目标是促进我们对代谢应激的理解， 2-氨基丙烯酸酯，中枢代谢反应中的专性中间体，以及控制它的蛋白质RidA。 此外，本研究的重点是高度保守的Rid蛋白家族，RidA是该家族的创始成员。 在目前的建议中，我们将：i）描述已经发展的额外的、不同的机制，以处理 类似的压力; ii）探索2-氨基丙烯酸酯压力的广度以及不同生物体如何处理它，以及iii） 定义额外的Rid蛋白的分子机制和细胞作用。本提案的目标是 通过化学，生物化学，分子遗传学，生物信息学和全球 接近。这项工作的动机是我们希望了解代谢应激产生的 在生长过程中产生反应性代谢物，如果不中和，它如何损害细胞成分， 并发现包括RidA在内的广泛保守的蛋白质家族的其他成员的作用。

SUMMARY A fundamental feature of a living system is its integrated network of biochemical pathways that respond to endogenous and environmental stresses. In humans, there is a strong connection between metabolic network dysfunction and disease. Metabolic strategies are conserved across biology, and insights obtained from model organisms provide the means to advance our understanding of general metabolic paradigms, which can often be extrapolated to higher organisms including humans. 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. Knowledge of metabolic processes and a mechanistic understanding of the function of unknown proteins is critical to efforts aimed at treating metabolic diseases, and to efforts targeting metabolism for rational drug design, synthetic biology, microbiome research, etc. The goal of the work proposed herein is to advance our understanding of the metabolic stress caused by the 2-aminoacrylate, an obligate intermediate in central metabolic reactions, and the protein that controls it, RidA. Further, this study focuses on the highly conserved Rid protein family, of which RidA is the founding member. In the current proposal we will: i) describe additional, distinct mechanisms that have evolved to deal with similar stress; ii) explore the breadth of 2-aminoacrylate stress and how different organisms handle it, and iii) define the molecular mechanism and cellular role of additional Rid proteins. The goals of this proposal will be accomplished through a combination of chemical, biochemical, molecular genetic, bioinformatics and global approaches. The work here is motivated by our desire to understand the metabolic stress generated by the production of reactive metabolites during growth, how it can damage cellular components if it is not neutralized, and discovering the role of additional members of the broadly conserved protein family that includes RidA.