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紧密相关的翻译后修饰。赖氨酸 - 乙酰化修饰系统功能障碍导致从癌症到神经退行性疾病和代谢疾病的严重疾病的发展。赖氨酸 - 乙酰基转移酶催化乙酰基酸酯从乙酰辅酶A到赖氨酸侧链的转移，并将脱乙酰基酶除去。脱乙酰基酶可以分为NAD+依赖性的Sirtuins和Zn2+依赖性的经典脱乙酰基酶（KDACS）。到目前为止，大多数对原核生物中脱乙酰基酶的研究都集中在单一sirtuin脱乙酰基酶上。我们采用了生物信息学方法，并确定了数千种新型古典KDAC在原核生物中。几个KDAC在致病性革兰氏阳性和革兰氏阴性细菌中编码，例如肺炎军团菌，弧菌霍乱弧菌，克雷伯氏菌肺炎和金黄色葡萄球菌。对于来自严重的人类病原体K.肺炎的一个KDAC，我们可以在Apo形式和具有抑制剂的复合物中求解晶体结构。在这项研究建议中，将结合合成生物学方法，结构生物学与微生物方法和质谱法相结合，以了解选定的新型原核生物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调节细胞过程的方法。由于细菌，尤其是致病性细菌，必须对环境改变并采用这些疾病的反应，因此赖氨酸乙酰化可能在这些过程中起重要作用。该项目中获得的结果不仅将有助于了解赖氨酸乙酰化在正常细菌生理学中的作用，而且对于探索一种应对赖氨酸乙酰化机制来治疗严重细菌感染的新型治疗策略的潜力也很有价值。考虑到多种耐药性细菌菌株在环境中的传播，该主题目前非常重要，当这些菌株在医院中传播时，这可能会带来严重的问题。