Investigating the structure, function, and regulation of polyamine acetyltransferases

项目摘要 该研究旨在研究细菌多胺乙酰转移酶的功能和调节 （PAAT）。这些酶属于大的Gcn 5相关的N-乙酰转移酶（GNAT）超家族，并且 乙酰化多种多胺，包括精胺、亚精胺和去甲亚精胺。主体功能 与细菌PAAT相关的是维持细胞内多胺浓度;然而， 越来越多的证据表明，PAAT可能在细菌生理学和致病机制中发挥更大的作用 比之前预期的要多。虽然PAAT已经在真核生物中得到了很好的研究，但在真核生物中存在显著的差距。 关于细菌PAAT身份、功能和调节的知识。此外，还有一个有限的 了解变构效应物和寡聚化如何调节PAAT功能，以及这些特性如何 影响PAAT在细菌生物膜和其他细胞过程中的作用。由于多胺与 细菌的毒力和致病机理，关于PAAT调节的知识对于开发有效的 细菌病原体的治疗方法。因此，所提出的研究的目标是确定 以及它们如何在致病性和非致病性细菌中受到调节。我们将调查 在接下来的五年里，以下关键问题：1）哪些细菌GNAT是PAAT？2)细菌如何 监管PAAT？和3）细菌PAAT如何调节细胞过程？这些问题的答案 将深入了解PAAT在细菌中的进化和分布，确定靶向治疗的策略， 并增加了细菌中PAAT功能和调节特性的基础知识。

PROJECT SUMMARY The proposed research seeks to study the functions and regulation of bacterial polyamine acetyltransferases (PAATs). These enzymes belong to the large Gcn5-related N-acetyltransferase (GNAT) superfamily, and acetylate a variety of polyamines including spermine, spermidine, and norspermidine. The main function associated with bacterial PAATs has been to maintain intracellular polyamine concentrations; however, increasing evidence has shown that PAATs likely play a larger role in bacterial physiology and pathogenesis than previously anticipated. While PAATs have been well-studied in eukaryotes, there is a significant gap in knowledge regarding bacterial PAAT identities, functions and regulation. Additionally, there is a limited understanding of how allosteric effectors and oligomerization regulate PAAT function, and how these properties effect PAAT roles in bacterial biofilms and other cellular processes. Since polyamines have been implicated in bacterial virulence and pathogenesis, knowledge about PAAT regulation is critical for developing effective therapeutics toward bacterial pathogens. Therefore, the goal of the proposed research is to determine the roles of PAATs and how they are regulated across pathogenic and non-pathogenic bacteria. We will investigate the following key questions over the next five years: 1) Which bacterial GNATs are PAATs?, 2) How are bacterial PAATs regulated?, and 3) How do bacterial PAATs regulate cellular processes?. The answers to these questions will yield insight into PAAT evolution and distribution across bacteria, identify strategies for targeted therapeutics, and add to the fundamental knowledge of PAAT function and regulatory properties in bacteria.