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）：氨基酰基-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。氨基酰基-TRNA合成酶通常属于两个无关的结构类别（I和II）之一，该规则的唯一例外是赖氨酸-TRNA合成酶。与它们的特殊结构和功能多样性一致，赖氨酸-TRNA合成酶已经与各种各样的细胞作用有关，与氨基酰基-TRNA合成分开，范围从抗生素耐药到转化控制。这些角色中的许多作用取决于赖氨酸-TRNA合成酶与其他蛋白质形成功能相互作用的能力，从而提供了一种模型系统来研究氨基酰基-TRNA合成酶的非规范作用。该提案的目标是：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典型TRNA的氨基酰化。 ii）研究赖氨酸-TRNA合成酶在建立抗生素耐药性中的作用。 iii）探测赖氨酸-TRNA合成酶在确定翻译效率作为多氨基酰基-TRNA合成酶复合物的组成部分方面的功能。这些实验的结果将揭示赖氨酸-TRNA合成酶在与翻译分开的细胞过程中的作用，并通过与其他蛋白质形成复合物来显示赖氨酸-TRNA合成酶如何提供新的和改变的功能。项目叙述性金黄色葡萄球菌，单核细胞增生李斯特氏菌和蜡状芽孢杆菌是具有潜在致命后遗症的食源性疾病的常见药物。 1类和2类赖氨酸-TRNA合成酶通过通过迄今为止仅定义的机制调节抗生素耐药性来促进这些细菌病原体的毒力。拟议的研究将定义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，并有助于确定是否可以将相应的途径用作抗感染剂的靶标。这项研究还将提供对一般AARS家族中功能多样性程度的进一步见解，AARS家族是一组新兴的抗微生物药物靶标。