Sirtuins and Metabolic Pathway Integration

描述（由申请人提供）：在自然界中，微生物面临着一系列挑战其生存的刺激。总的来说，这些刺激对复杂的快速反应机制的进化施加了强大的选择压力，这些机制可以通过调节不同生物分子的功能来有效地维持体内平衡。毫不奇怪，生物学家有兴趣了解这些机制如何工作，它们如何被调节，以及它们如何被整合到细胞调节回路中。PI的实验室研究通过化学修饰控制蛋白质功能，重点是可逆的赖氨酸酰化（RLA）。十年前，PI的研究小组报告了原核生物中RLA的第一个证据，这一发现引起了人们的极大兴趣。在很短的时间内，RLA已经成为一个 翻译后修饰在其广度和对细胞复杂代谢网络动力学的影响方面与磷酸化竞争。近年来，PI的研究小组报道了RLA对中枢细胞过程的影响，如细胞运动、基因表达、碳代谢、能量和辅酶A稳态。 PI的实验室研究通过RLA控制蛋白质功能。R 01-GM 062203资助的长期目标是了解RLA对细胞功能的贡献。PI的团队将继续应用全面的遗传学，分子生物学，生物化学，结构和系统范围的方法来回答有关RLA功能机制的基本问题。本报告建议开展的工作旨在：i）了解乙酰转移酶如何识别其蛋白质底物的分子细节; ii）深入了解乙酰转移酶功能的机制; iii）更好地了解蛋白质如何进化以逃避RLA控制;以及iv）定义将RLA整合到细胞复杂代谢网络中的调控回路。

DESCRIPTION (provided by applicant): In nature, microbes face a spectacular array of stimuli that challenge their survival. Collectively, these stimuli exert a strong selective pressure for th evolution of sophisticated, rapid-response mechanisms that can efficiently maintain homeostasis through the modulation of functions of diverse biomolecules. Not surprisingly, biologists are interested in understanding how these mechanisms work, how they are regulated, and how they are integrated into the cellular regulatory circuits. The PI's laboratory studies the control of protein function by chemical modifications, with an emphasis on reversible lysine acylation (RLA). Ten years ago, the PI's group reported the first evidence of RLA in prokaryotes, a discovery that elicited a great deal of interest. In a short period of time, RLA has emerged as a posttranslational modification that rivals phosphorylation in terms of its breadth and impact on the dynamics of the complex metabolic network of the cell. In recent years, the PI's group has reported the impact of RLA on central cellular processes such as cell motility, gene expression, carbon metabolism, energy and coenzyme A homeostasis. The PI's laboratory studies the control of protein function by RLA. The long-term goal of the work supported by grant R01-GM062203 is to understand the contributions of RLA to cell function. The PI's group will continue to apply comprehensive genetic, molecular biological, biochemical, structural, and system-wide approaches to answer fundamental questions regarding the mechanism of RLA function. Work proposed herein seeks to: i) learn the molecular details of how acetyltransferases recognize their protein substrates; ii) gain insights into the mechanism of acetyltransferase function; iii) gain a better understanding of how proteins evolve to escape RLA control; and iv) define the regulatory circuit that integrates RLA into the complex metabolic network of the cell.