REGULATION OF LIPID METABOLISM IN BACTERIA

细菌脂质代谢的调节

• 批准号: 7886036
• 负责人: Charles O Rock
• 金额: $ 7.08万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886036
• 关键词: 3-Dimensional; Active Sites; Acyl Carrier Protein; Acyl Coenzyme A; Acyltransferase; Affect; Anabolism; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Bacterial Physiology; Binding; Biochemical; Biological Models; Cell physiology; Cells; Characteristics; Complement; Complex; Development; Docking; Enzymes; Escherichia coli; Evolution; Fatty Acids; Feedback; Genes; Genomics; Glycerol; Glycogen Branching Enzyme; Goals; Gram-Positive Bacteria; Grant; Homologous Gene; Investigation; Lipids; Maps; Membrane; Membrane Lipids; Modeling; Molecular; Mutation; Mycobacterium tuberculosis; Organism; Oxidoreductase; Pathway interactions; Pattern; Phospholipids; Positioning Attribute; Prosthesis; Protein Synthesis Inhibition; Proteins; Regulation; Research; Research Personnel; Roentgen Rays; Role; Set protein; Signal Transduction; Site; Site-Directed Mutagenesis; Streptococcus pneumoniae; Structure; Substrate Specificity; Surface; Synthase I; System; Techniques; Technology; Testing; Unsaturated Fatty Acids; Weight; Work; base; cell growth; design; drug sensitivity; enoyl reductase; fatty acid biosynthesis; in vivo Model; inhibitor/antagonist; insight; lipid biosynthesis; lipid metabolism; multidisciplinary; mutant; novel; novel therapeutics; pathogen; physical property; programs; research study; response; sensor; structural biology; thiolactomycin; tool

The long-term goal of this project is to understand the mechanisms that regulate bacterial membrane lipid biosynthesis and explore the structure, function and diversity of the enzymes involved in this pathway. The study of Escherichia coli has historically served as the paradigm for bacterial lipid metabolism. The evolution of lipid biosynthesis as a focal point for the development of novel therapeutics and the availability of a wealth of genomic sequences has stimulated the exploration of these pathways in important pathogens. The discovery of two novel enoyl-[acyl carrier protein] reductases in Gram-positive bacteria during the last grant period highlights the importance of this avenue of research. We have developed the tools for a multidisciplinary attack on this important problem that will incorporate the techniques of structural biology into all facets of the research. The research plan builds on the important discoveries made during the last grant period and is organized into three subject areas. The enoyl reductase step is a key regulator of fatty acid elongation and the target for widely used antibacterial agents. In the first aim, we will investigate the biochemical mechanism, structure and function of the enoyl reductase and expand this work to include the two newly discovered enoyl reductases of Gram-positive bacteria as well as the universally expressed and highly conserved (3-ketoacyl-[acyl carrier protein] reductase. Lipid metabolism is a vital facet of bacterial physiology and in the second aim we will define the regulatory mechanisms that integrate fatty acid biosynthesis into cell physiology and coordinate membrane lipid formation with macromolecular biosynthesis. Our investigation of fatty acid biosynthesis in Gram-positive bacteria will focus on elucidating the pathways for unsaturated fatty acid synthesis in an important pathogen. The condensing enzymes are key regulators of fatty acid composition, and in the third aim, we will define the molecular characteristics that determine their substrate specificity, use these enzymes as a model for defining the critical 3- dimensional features necessary for the docking of acyl carrier protein, and determine the mechanism of action of a broad-spectrum antibiotic, thiolactomycin. The results of these investigations will provide important new information on the structure, function, diversity and regulation of fatty acid biosynthesis that will contribute to the basic understanding of bacterial physiology and complement the development of novel antibacterialtherapeutics.

该项目的长期目标是了解调节细菌膜脂质的机制 生物合成并探索参与该途径的酶的结构、功能和多样性。研究 大肠杆菌历史上一直作为细菌脂质代谢的范例。脂质的演变 生物合成作为新疗法开发和丰富基因组的可用性的焦点 序列刺激了对重要病原体中这些途径的探索。两本小说的发现 最后资助期间革兰氏阳性细菌中的烯酰基-[酰基载体蛋白]还原酶强调了 这一研究途径的重要性。我们开发了针对此问题进行多学科攻击的工具 这是一个重要的问题，它将结构生物学技术纳入研究的各个方面。这 研究计划建立在上一个资助期间取得的重要发现的基础上，分为三个部分 学科领域。烯酰还原酶步骤是脂肪酸延伸的关键调节因子，也是广泛应用的目标 抗菌剂。第一个目标是研究该蛋白的生化机制、结构和功能。 烯酰还原酶并将这项工作扩展到包括两种新发现的革兰氏阳性菌烯酰还原酶 细菌以及普遍表达和高度保守的（3-酮酰基-[酰基载体蛋白]还原酶。 脂质代谢是细菌生理学的一个重要方面，在第二个目标中，我们将定义调节 将脂肪酸生物合成整合到细胞生理学中并协调膜脂质形成的机制 与大分子生物合成。我们对革兰氏阳性菌中脂肪酸生物合成的研究将集中于 阐明重要病原体中不饱和脂肪酸合成的途径。凝结 酶是脂肪酸组成的关键调节剂，在第三个目标中，我们将定义分子 决定其底物特异性的特征，使用这些酶作为定义关键 3- 酰基载体蛋白对接所需的尺寸特征，并确定其作用机制 一种广谱抗生素，硫代乳霉素。这些调查的结果将提供重要的新信息 有关脂肪酸生物合成的结构、功能、多样性和调节的信息，将有助于 对细菌生理学的基本了解并补充新型抗菌疗法的开发。