Structural and functional studies on novel bacterial lysine-deacetylases and their roles in bacterial physiology and during bacterial infection.

新型细菌赖氨酸脱乙酰酶的结构和功能研究及其在细菌生理学和细菌感染过程中的作用。

• 批准号: 449703098
• 负责人: Professor Dr. Michael Lammers
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/449703098?language=en
• 关键词: Structural; functional; studies; novel; bacterial

Lysine-acetylation is a post-translational modification that is tightly connected to the cellular metabolism. Dysfunction in the lysine-acetylation modifcation system results in the development of severe diseases ranging from cancer to neurodegenerative diseases and metabolic diseases. Lysine-acetyltransferases catalyze the transfer of the acetyl-moiety from acetyl-CoA to the lysine side chain, and deacetylases remove it. Deacetylases can be classified into NAD+-dependent Sirtuins and Zn2+-dependent classical deacetylases (KDACs). So far, most research on deacetylases in prokaryotes focussed on a single sirtuin deacetylase. We applied a bioinformatics approach and identified thousands of novel classical KDACs in prokaryotes. Several KDACs are encoded in pathogenic Gram-positive and Gram-negative bacteria, such as Legionella pneumophilae, Vibrio cholerae, Klebsiella pneumoniae and Staphylococcus aureus. For one KDAC from K. pneumoniae, a severe human pathogen, we could solve crystal structures in the apo-form and in the complexes with inhibitors. In this research proposal will combine synthetic biological approaches, structural biology with microbiological approaches and mass-spectrometry to understand how selected novel prokaryotic KDACs affects bacterial physiology and pathophysiology. Post-translational lysine-acetylation is a way to sense metabolic changes in the cellular environment and to translate these changes to regulate cellular processes by altering protein function. As bacteria, and particularly pathogenic bacteria, have to respond fast to alterations in their environment and to adopt to these conditions, lysine acetylation might play an important role in these processes. The results obtained in this project will not only help to understand the role of lysine acetylation in normal bacterial physiology, it will also be valuable to explore the potential of a novel therapeutic strategy tackling the lysine acetylation machinery to treat severe bacterial infections. This topic is currently highly important considering the spread of multi-resistant bacterial strains in the environment, which can lead severe problems when those strains spread in hospitals.

赖氨酸乙酰化是一种与细胞代谢密切相关的翻译后修饰。赖氨酸乙酰化修饰系统的功能障碍会导致癌症、神经退行性疾病和代谢性疾病等严重疾病的发生。赖氨酸乙酰转移酶催化乙酰基部分从乙酰辅酶A转移到赖氨酸侧链，脱乙酰酶将其去除。脱乙酰酶可分为 NAD+ 依赖性 Sirtuins 和 Zn2+ 依赖性经典脱乙酰酶 (KDAC)。迄今为止，大多数关于原核生物脱乙酰酶的研究都集中在单一的沉默调节蛋白脱乙酰酶上。我们应用生物信息学方法并在原核生物中鉴定了数千种新型经典 KDAC。多种 KDAC 在致病性革兰氏阳性和革兰氏阴性细菌中编码，例如嗜肺军团菌、霍乱弧菌、肺炎克雷伯菌和金黄色葡萄球菌。对于来自肺炎克雷伯菌（一种严重的人类病原体）的 KDAC，我们可以解析脱辅基形式和与抑制剂复合物的晶体结构。在本研究提案中，将结合合成生物学方法、结构生物学与微生物学方法和质谱法，以了解选定的新型原核 KDAC 如何影响细菌生理学和病理生理学。翻译后赖氨酸乙酰化是一种感知细胞环境中代谢变化并通过改变蛋白质功能来转化这些变化以调节细胞过程的方法。由于细菌，特别是病原菌，必须对其环境的变化做出快速反应并适应这些条件，赖氨酸乙酰化可能在这些过程中发挥重要作用。该项目获得的结果不仅有助于了解赖氨酸乙酰化在正常细菌生理学中的作用，而且对于探索解决赖氨酸乙酰化机制的新型治疗策略治疗严重细菌感染的潜力也很有价值。考虑到多重耐药菌株在环境中的传播，这个主题目前非常重要，当这些菌株在医院传播时可能会导致严重的问题。