MEMBERS OF THE YJGF SUPERFAMILY NEUTRALIZE ENDOGENOUS METABOLIC STRESSORS

描述(申请人提供)：生命系统的一个基本特征是一个综合的生化途径网络，可以对环境施加的压力做出反应。微生物，特别是那些具有遗传系统的微生物，提供了一个在技术上顺从的系统来表征新陈代谢过程和应激反应。代谢策略在生物学中是保守的，从微生物系统中获得的见解将有助于我们对一般代谢范式的理解。我研究的长期目标是帮助理解新陈代谢成分及其参与的过程。对代谢过程的严格理解对于预测细胞对环境变化的反应、努力开发代谢建模策略以及针对代谢进行合理的药物设计和/或生产小分子等至关重要。这项工作的目标是描述由生长过程中产生的反应性代谢物引起的代谢应激，并了解中和这种应激的蛋白质家族。本研究的重点是一种细菌蛋白(YjgF)，它是高度保守的蛋白质家族的成员，可以中和活性氮物种(例如烯胺类)。在目前的方案中，我们将1)确定被YjgF蛋白中和的应激源，2)确定不中和这种代谢应激的分子后果，3)探索YjgF家族中序列与功能差异之间的关系。这项提议的目标将通过使用现代化学、生化、生物物理、分子、遗传和生物信息技术来实现。这里提出的工作的动机是我们希望了解生长过程中通过产生活性代谢物而产生的代谢应激，如果不中和这些代谢物，这些代谢物可能会损害细胞成分。

DESCRIPTION (provided by applicant): A fundamental feature of a living system is an integrated network of biochemical pathways that can respond to stresses applied by the environment. Microbes, particularly those with a genetic system, provide a technically amenable system to characterize metabolic processes and stress responses. Metabolic strategies are conserved across biology, and insights obtained from microbial systems will contribute to our understanding of general metabolic paradigms. The long-term goal of my research is to contribute to the understanding of metabolic components and the processes they participate in. A rigorous understanding of metabolic processes is critical in efforts to predict the response of cells to environmental change, efforts to develop metabolic modeling strategies and efforts targeting metabolism for rational drug design and/or production of small molecules, to name a few. The goal of the work herein is to characterize a metabolic stress that results from reactive metabolites generated during growth, and to understand the family of proteins that neutralize this stress. This study focuses on a bacterial protein (YjgF) that is a member of highly conserved protein family that neutralizes reactive nitrogen species (e.g. enamines). In the current proposal, we will i) identify the stressors neutralized by the YjgF protein, ii) define the molecular consequences of not neutralizing this metabolic stress and iii) explore the relationship between sequence and functional divergence in the YjgF family. The goals of this proposal will be accomplished through the use of modern chemical, biochemical, biophysical, molecular, genetic and bioinformatic techniques. The work proposed here is motivated by our desire to understand the metabolic stress generated during growth by the production of reactive metabolites that can damage cellular components if they are not neutralized.