The Mevalonate Pathway in Streptococcus

链球菌中的甲羟戊酸途径

• 批准号: 7193446
• 负责人: Thomas S. Leyh
• 金额: $ 52.51万
• 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/7193446
• 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

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：肺炎链球菌（SP）每天夺去近 4000 人的生命，其中大多数是五岁以下的儿童。生物体进化出耐药机制的能力已经产生了能够耐受我们的“最后一道防线”抗生素的菌株。该实验室最近发现二磷酸甲羟戊酸（DPM）是甲羟戊酸途径的中间体，是SP甲羟戊酸激酶（MK）的有效变构抑制剂，并且它不抑制人类同工酶。甲羟戊酸途径对于小鼠肺部生物体的生存至关重要。 DPM 和变构位点提供了先导化合物和靶标，为开发有助于根除这种疾病的新型抗生素提供了机会。我们的初步数据表明，基于这些原理的化合物能够杀死富媒体中的感染性 SP。该提案将结构、功能和合成整合到一个项目中，旨在探索和定义 SP 中构成甲羟戊酸途径的三种酶，并以此为抗生素的设计和合成提供基础。该计划将产生的信息具有相当大的基础科学价值。组成该途径的三种酶中的每一种都是 GHMP 激酶蛋白超家族的成员，其生物医学相关性延伸到孤儿疾病和白内障形成。我们已经从 SP 确定了 MK 的结构，并且即将确定 DPM 抑制的与底物结合的复合物的结构。这些结构定义了 MK 靶标，并将揭示 DPM 结合如何破坏化学反应。我们还确定了来自 SP 的磷酸甲羟戊酸激酶 (PMK) 三元复合物的结构，这提出了有趣的机制问题，强调了 PMK 的独特和家族结构元素。二磷酸甲羟戊酸脱羧酶 (DPM-DC) 是一种令人着迷的酶，可通过碳阳离子过渡态使 DPM 脱羧。我们将通过定义其过渡态结构并监测配体和中间复合物的形成来探索 DPM-DC 机制，从而为该机制类别创建先进的催化范例。