The Mevalonate Pathway in Streptococcus

链球菌中的甲羟戊酸途径

• 批准号: 7365219
• 负责人: Thomas S. Leyh
• 金额: $ 53.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365219
• 关键词: Active Sites; Address; Age; Allosteric Site; Antibiotics; Binding; Carbon; Carboxy-Lyases; Catalysis; Cataract; Cations; Chemistry; Child; Class; Complex; Daily; Data; Decarboxylation; Dependence; Disease; Electronics; Electrons; Elements; Enzymes; Event; Family; Family member; Free Energy; Hand; Human; Hydroxyl Radical; Isoenzymes; Isotopes; Kinetics; Laboratories; Lead; Life; Ligand Binding; Ligands; Lung; Methods; Mevalonate kinase; Monitor; Mono-S; Mus; Nature; Object Attachment; Organism; Orphan Disease; Pathway interactions; Phosphomevalonate kinase; Phosphotransferases; Property; Protein Kinase; Proteins; Rate; Reaction; Resolution; Staging; Streptococcus; Streptococcus pneumoniae; Structure; System; Testing; Time; X ray diffraction analysis; X-Ray Diffraction; base; design; fascinate; inhibitor/antagonist; inorganic phosphate; killings; member; mevalonate; novel; programs; resistance mechanism; tool

Streptococcus pneumonia (SP)takes the lives of nearly 4000 people daily, the majority of whom are children below the age of five. The organism's ability to evolve resistance mechanisms has produced strains capable of tolerating our "last line of defense" antibiotics. This laboratory recently discovered that diphosphomevalonate (DPM), an intermediate in the mevalonate pathway, is a potent allosteric inhibitor of the SP mevalonate kinase (MK), and that it does not inhibit the human isozyme. The mevalonate pathway is essential for survival of the organism in mouse lung. DPM and the allosteric site offer a lead compound and target that provide an opportunity to develop a new class of antibiotics that could help eradicate this disease. Our preliminary data demonstrate that compounds based on these principles are capable of killing infectious SP in rich media. This proposal integrates structure, function and synthesis in a project designed to explore and define the three enzymes that comprise the mevalonate pathway in SP, and,in so doing, provide a basis for the design and synthesis of antibiotics. The information that this program will create is of considerable fundamental scientific value. Each of the three enzymes that comprise the pathway is a member of the GHMP kinase protein superfamily, whose biomedical relevance extends to both orphan diseases and cataract formation. We have determined the structure of MK from SP, and the structure of the DPM-inhibited complex with bound substrates is imminent. These structures define the MK-target and will reveal how DPM binding disrupts chemistry. We've also determined the structure of a ternary complex of phosphomevalonate kinase (PMK)from SP, which raises intriguing mechanistic issues that emphasize both the unique and familial structural elements of PMK. Diphosphomevalonate decaboxylase (DPM-DC) is a fascinating enzyme that decarboxylates DPM via a carbocationic transition-state. We will explore the DPM-DC mechanism by defining its transition-state structures and monitoring the formation of ligand and intermediate complexes to create an advanced catalytic paradigm for this mechanistic class.

肺炎链球菌(SP)每天夺去近4000人的生命，其中大部分是儿童 五岁以下的儿童。生物体进化抗性机制的能力已经产生了能够 耐受我们的“最后一道防线”抗生素。这个实验室最近发现 甲氧丙戊酸途径的中间体二磷戊酸(DPM)是一种有效的变构抑制剂。 SP甲氧丙戊酸激酶(MK)，它不抑制人类同工酶。甲氧戊酸途径是 对这种生物在小鼠肺中的生存是必不可少的。DPM和变构位置提供了先导化合物和 目标是提供机会开发一种新类别的抗生素，以帮助根除这种疾病。 我们的初步数据表明，基于这些原理的化合物能够杀死传染性疾病 富媒体中的SP。该方案集结构、功能和合成于一体，旨在探索 并定义了构成SP中甲氧戊酸途径的三种酶，并在这样做的过程中，提供了一个基础 用于抗生素的设计和合成。这个程序将产生的信息是相当可观的 基本的科学价值。构成该途径的三种酶中的每一种都是 GHMP蛋白超家族，其生物医学意义延伸到孤儿疾病和白内障 队形。我们从SP中确定了MK的结构，并确定了DPM抑制的结构 与底物结合的复合体迫在眉睫。这些结构定义了MK目标，并将揭示DPM如何 结合会破坏化学作用。我们还测定了一个三元配合物的结构。 来自SP的KEK(PMK)，它提出了有趣的机制问题，强调了独特的和 PMK的家族结构要素。二磷酸戊酸脱羧酶(DPM-DC)是一种迷人的 通过碳阳离子过渡态使DPM脱羧的酶。我们将探索DPM-DC 通过定义其过渡态结构和监测配体和中间体的形成来实现其机理 复合体为这个机械类创建了一个高级催化范例。