STRUCTURAL STUDIES OF PROTEINS INVOLVED IN THE LPS BIOSYNTHETIC PATHWAY

LPS 生物合成途径相关蛋白质的结构研究

• 批准号: 8363381
• 负责人: MURRAY JUNOP
• 金额: $ 2.81万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363381
• 关键词: Anabolism; Antibiotics; Cell Membrane Permeability; Cell Wall; Commit; Crystallography; Drug Delivery Systems; Funding; Goals; Grant; Heptoses; Infection; Isomerase; Light; Lipid A; Lipopolysaccharide Biosynthesis Pathway; Lipopolysaccharides; National Center for Research Resources; Pathway interactions; Phenotype; Polysaccharides; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Side; Source; Synchrotrons; United States National Institutes of Health; combat; cost; design; inhibitor/antagonist

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Lipopolysaccharide (LPS) is a major component of the Gram-negative bacterial cell wall. LPS is comprised of three components: lipid A, core polysaccharide (Kdo and one or more heptose residues), and polysaccharide side chains. LPS biosynthesis that is halted prior to heptose addition results in a deep-rough phenotype and membrane permeability to antibiotics is increased. For this reason, the heptose biosynthetic pathway has been marked as a potential drug target. Our goal is to determine the mechanism of GmhA, an isomerase that catalyzes the first committed step of ADP-L-glycero-¿?-manno-heptose biosynthesis as well as GmhB and HldE which are also key players in LPS biosynthesis. Determination of the enzymatic mechanisms used by these proteins will aid in the rational design of inhibitors of GmhA, GmhB and HldE as a means to combat Gram negative infection.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 脂多糖（LPS）是革兰氏阴性细菌细胞壁的主要成分。LPS由三种组分组成：脂质A、核心多糖（Kdo和一个或多个庚糖残基）和多糖侧链。在添加庚糖之前停止的LPS生物合成导致深粗糙表型，并且膜对抗生素的渗透性增加。因此，庚糖生物合成途径已被标记为潜在的药物靶点。我们的目标是确定GmhA的机制，GmhA是一种异构酶，催化ADP-L-glycero-？甘露庚糖生物合成以及GmhB和HldE，它们也是LPS生物合成中的关键参与者。确定这些蛋白质使用的酶促机制将有助于合理设计GmhA、GmhB和HldE抑制剂，作为对抗革兰氏阴性菌感染的手段。