Biochemistry of lysyl-tRNA synthetases

赖氨酰-tRNA 合成酶的生物化学

基本信息

批准号：
7386232
负责人：
MICHAEL IBBA
金额：
$ 30.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386232
关键词：
Amino Acids Amino Acyl Transfer RNA Amino Acyl-tRNA Synthetases Aminoacylation Anaplasma phagocytophilum Anti-Infective Agents Antibiotic Resistance Antibiotics Antimicrobial Cationic Peptides Archaea Bacillus cereus Bacteria Bartonella Biochemistry Biological Models Borrelia Brucella Cell physiology Class Complex Disease Drug Delivery Systems Ehrlichia Elements Enzymes Eukaryota Eukaryotic Cell Family Genetic Code Homologous Gene Individual Lead Ligase Lipids Listeria monocytogenes Lysine-Specific tRNA Lysine-tRNA Ligase Membrane Pathway interactions Peptide Elongation Factor 1 Peptides Protein Biosynthesis Proteins Range Research Resistance Rickettsia Role Specificity Staphylococcus aureus Substrate Specificity Transfer RNA Translations Treponema pallidum Ursidae Family Virulence Work antimicrobial drug foodborne insight novel paralogous gene pathogen pathogenic bacteria research study resistance factors

项目摘要

DESCRIPTION (provided by applicant): The aminoacyl-tRNA synthetases are responsible for pairing amino acids and tRNAs during translation and are crucial in defining the genetic code. Aminoacyl-tRNA synthetases normally belong to one of two unrelated structural classes (I and II), the only known exception to this rule being the lysyl-tRNA synthetases. Consistent with their exceptional structural and functional diversity, the lysyl-tRNA synthetases have been implicated in a wide variety of cellular roles separate from aminoacyl-tRNA synthesis ranging from antibiotic resistance to translational control. Many of these roles depend on the ability of lysyl-tRNA synthetases to form functional interactions with other proteins, providing a model system to study non-canonical roles of the aminoacyl-tRNA synthetases. The objectives of this proposal are to: i) Determine how interactions between class I and II lysyl-tRNA synthetases lead to the aminoacylation of non-canonical tRNAs. ii) Investigate the role of lysyl-tRNA synthetases in establishing antibiotic resistance. iii) Probe the function of lysyl-tRNA synthetase in determining translational efficiency as a component of a multi-aminoacyl-tRNA synthetase complex. The results of these experiments will reveal roles for lysyl-tRNA synthetases in cellular processes separate from translation, and show how lysyl-tRNA synthetases provide new and altered functions by forming complexes with other proteins. Project Narrative Staphylococcus aureus, Listeria monocytogenes and Bacillus cereus are common agents of foodborne disease with potentially fatal sequelae. The class 1 and class 2 lysyl-tRNA synthetases contribute to the virulence of these bacterial pathogens by modulating antibiotic resistance through mechanisms which to date have only been minimally defined. The proposed studies will define the roles of class 1 and class 2 lysyl-tRNA synthetases in establishing antibiotic resistance, and help determine if the corresponding pathways can be used as targets for anti-infective agents. The study will also provide further insights into the degree of functional diversity within the aaRS family in general, an emerging group of anti-microbial drug targets.

描述（由申请人提供）：氨酰基-tRNA 合成酶负责在翻译过程中配对氨基酸和 tRNA，并且对于定义遗传密码至关重要。氨酰-tRNA 合成酶通常属于两个不相关的结构类别（I 和 II）之一，唯一已知的例外是赖氨酰-tRNA 合成酶。与其特殊的结构和功能多样性相一致，赖氨酰-tRNA合成酶与氨酰-tRNA合成不同，涉及从抗生素耐药性到翻译控制等多种细胞作用。其中许多作用取决于赖氨酰-tRNA 合成酶与其他蛋白质形成功能性相互作用的能力，为研究氨酰-tRNA 合成酶的非规范作用提供了模型系统。该提案的目标是： i) 确定 I 类和 II 类赖氨酰-tRNA 合成酶之间的相互作用如何导致非规范 tRNA 的氨酰化。 ii) 研究赖氨酰-tRNA 合成酶在建立抗生素耐药性中的作用。 iii) 探讨赖氨酰-tRNA 合成酶作为多氨酰-tRNA 合成酶复合物的组成部分在确定翻译效率中的功能。这些实验的结果将揭示赖氨酰-tRNA 合成酶在与翻译无关的细胞过程中的作用，并展示赖氨酰-tRNA 合成酶如何通过与其他蛋白质形成复合物来提供新的和改变的功能。项目叙述金黄色葡萄球菌、单核细胞增多性李斯特菌和蜡状芽孢杆菌是食源性疾病的常见病原体，具有潜在的致命后遗症。 1 类和 2 类赖氨酰-tRNA 合成酶通过调节抗生素耐药性来增强这些细菌病原体的毒力，而迄今为止，这些机制仅得到了最低限度的明确。拟议的研究将确定 1 类和 2 类赖氨酰-tRNA 合成酶在建立抗生素耐药性中的作用，并帮助确定相应的途径是否可以用作抗感染药物的靶点。该研究还将进一步深入了解 aaRS 家族（一组新兴的抗微生物药物靶点）的功能多样性程度。