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：
10260571
负责人：
Diana M. Downs
金额：
$ 34.04万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10260571
关键词：
Active Sites Address Animal Model Bacteria Bacterial Model Behavior Biochemical Biochemical Genetics Biochemical Pathway Bioinformatics Biological Assay Biological Models Biology Campylobacter jejuni Catabolism Categories Cells Characteristics Chemicals Data Deaminase Disease Drug Design Enzymes Escherichia coli Excision Family Family member Funding Genes Genetic Genome Goals Grant Growth Human Knowledge Laboratories Life Metabolic Metabolic Control Metabolic Diseases Metabolic stress Metabolism Molecular Molecular Genetics Nature Organism Physiological Prevention Process Production Protein Family Proteins Pseudomonas aeruginosa Reaction Research Role Saccharomyces cerevisiae Salmonella enterica Stress Substrate Specificity System Uracil Water Work base biological systems cell injury environmental stressor enzyme activity fitness improved in vivo insight man member metabolic abnormality assessment metabolomics microbiome research network dysfunction prevent response small molecule stressor synthetic biology transcriptomics

项目摘要

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.

概括生命系统的一个基本特征是其集成的生化途径网络，该网络响应内源性和环境压力。在人类中，代谢网络之间存在着紧密的联系功能障碍和疾病。代谢策略在整个生物学中都是保守的，并且从模型中获得的见解生物体提供了增进我们对一般代谢范式的理解的手段，这通常可以可以推断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稳健性和冗余性，并定义代谢成分和他们参与的过程。代谢过程的知识和对代谢过程的机械理解未知蛋白质的功能对于治疗代谢疾病以及靶向治疗的努力至关重要合理药物设计、合成生物学、微生物组研究等的代谢。本文提出的工作目标是增进我们对由代谢应激引起的代谢应激的理解。 2-氨基丙烯酸酯，中央代谢反应中的一种专性中间体，以及控制它的蛋白质 RidA。此外，本研究重点关注高度保守的 Rid 蛋白家族，RidA 是该家族的创始成员。在当前的提案中，我们将： i) 描述额外的、独特的机制，这些机制已经发展来处理类似的压力； ii) 探索 2-氨基丙烯酸酯应激的广度以及不同生物体如何应对它，以及 iii) 定义其他 Rid 蛋白的分子机制和细胞作用。该提案的目标是通过化学、生物化学、分子遗传学、生物信息学和全球科学的结合来完成接近。这项工作的动机是我们希望了解由生长过程中反应性代谢物的产生，如果不被中和，它会如何损害细胞成分，并发现包括 RidA 在内的广泛保守蛋白家族的其他成员的作用。