Biochemistry of lysyl-tRNA synthetases

赖氨酰-tRNA 合成酶的生物化学

• 批准号: 7555043
• 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
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555043
• 关键词: Amino Acids; Amino Acyl Transfer RNA; Amino Acyl-tRNA Synthetases; Aminoacylation; Anaplasma phagocytophilum; Anti-Infective Agents; Antibiotic Resistance; Archaea; Bacillus cereus; Bacteria; Bartonella; Biochemistry; Biological Models; Borrelia; Brucella; Cell physiology; Complex; Disease; Drug Delivery Systems; Ehrlichia; Elements; Enzymes; Eukaryota; Family; Genetic Code; Homologous Gene; Individual; Lead; Ligase; Lipids; Listeria monocytogenes; Lysine-Specific tRNA; Lysine-tRNA Ligase; Membrane; Pathway interactions; Peptide Antibiotics; Peptide Elongation Factor 1; Peptides; Protein Biosynthesis; Proteins; Research; Resistance; Rickettsia; Role; Specificity; Staphylococcus aureus; Substrate Specificity; Transfer RNA; Translations; Treponema pallidum; Ursidae Family; Virulence; Work; antimicrobial drug; antimicrobial peptide; foodborne; insight; novel; paralogous gene; pathogen; pathogenic bacteria; research study; resistance factors

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）：在翻译过程中，氨基酰基- trna合成酶负责氨基酸和trna的配对，对定义遗传密码至关重要。氨酰基- trna合成酶通常属于两个不相关的结构类（I和II）之一，唯一已知的例外是赖氨酸- trna合成酶。与其特殊的结构和功能多样性相一致，赖氨酸- trna合成酶与氨基酰基- trna合成不同，涉及从抗生素抗性到翻译控制的各种细胞作用。许多这些作用依赖于赖氨酸- trna合成酶与其他蛋白质形成功能相互作用的能力，为研究氨基- trna合成酶的非规范作用提供了一个模型系统。本提案的目标是：i)确定i类和II类赖氨酸- trna合成酶之间的相互作用如何导致非规范trna的氨基酰化。ii)研究赖氨酸- trna合成酶在抗生素耐药过程中的作用。iii)探索赖氨酸- trna合成酶作为多氨基酰基- trna合成酶复合物的组成部分在决定翻译效率方面的功能。这些实验的结果将揭示赖氨酸- trna合成酶在细胞过程中与翻译分离的作用，并显示赖氨酸- trna合成酶如何通过与其他蛋白质形成复合物提供新的和改变的功能。金黄色葡萄球菌，单核细胞增生李斯特菌和蜡样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类赖氨酸- trna合成酶通过调节抗生素耐药性的机制对这些细菌病原体的毒力起作用，迄今为止，这些机制的定义还很有限。拟建的研究将明确1类和2类赖氨酸- trna合成酶在建立抗生素耐药性中的作用，并有助于确定相应的途径是否可以作为抗感染药物的靶点。该研究还将进一步深入了解aaRS家族的功能多样性程度，这是一组新兴的抗微生物药物靶点。