The Mevalonate Pathway in Streptococcus

链球菌中的甲羟戊酸途径

• 批准号: 7768421
• 负责人: Thomas S. Leyh
• 金额: $ 55.73万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768421
• 关键词: Active Sites; Address; Age; Allosteric Site; Antibiotics; Binding; Carbon; Carboxy-Lyases; Catalysis; Cataract; Cations; Chemistry; Child; Complex; 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; Organism; Orphan Disease; Pathway interactions; Phosphomevalonate kinase; Phosphotransferases; Property; Protein Kinase; Proteins; 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，其中大多数是儿童 五岁以下。生物体进化出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。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，是一种有效的变构抑制剂 SP 甲羟戊酸激酶 (MK)，并且它不抑制人类同工酶。甲羟戊酸途径是 对于小鼠肺部有机体的生存至关重要。 DPM 和变构位点提供先导化合物并 目标提供了开发新型抗生素的机会，有助于根除这种疾病。 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病毒 富媒体中的 SP。该提案将结构、功能和综合整合到一个旨在探索的项目中 并定义了 SP 中构成甲羟戊酸途径的三种酶，并在此过程中提供了基础 用于抗生素的设计和合成。该程序将创建的信息非常重要 基本科学价值。组成该途径的三种酶中的每一种都是 GHMP 激酶蛋白超家族，其生物医学相关性延伸至孤儿疾病和白内障 形成。我们已经从SP中确定了MK的结构，以及DPM抑制的结构 与结合底物形成复合物迫在眉睫。这些结构定义了 MK 目标并将揭示 DPM 如何 结合会破坏化学反应。我们还确定了磷酸甲羟戊酸三元复合物的结构 来自 SP 的激酶（PMK），这提出了有趣的机制问题，强调独特和 PMK 的家族结构要素。二磷酸甲羟戊酸十羧化酶 (DPM-DC) 是一种令人着迷的酶 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并监测配体和中间体的形成来机制 配合物为该机械类创建先进的催化范例。

项目成果

Structure of the ternary complex of phosphomevalonate kinase: the enzyme and its family.

• DOI: 10.1021/bi900537u
• 发表时间: 2009-07-14
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Andreassi, John L., II;Vetting, Matthew W.;Bilder, Patrick W.;Roderick, Steven L.;Leyh, Thomas S.
• 通讯作者: Leyh, Thomas S.

Backbone 1H, 13C, 15N NMR assignments of the unliganded and substrate ternary complex forms of mevalonate diphosphate decarboxylase from Streptococcus pneumoniae.

肺炎链球菌甲羟戊酸二磷酸脱羧酶的未配体和底物三元复合物形式的主链 1H、13C、15N NMR 归属。

• DOI: 10.1007/s12104-010-9255-4
• 发表时间: 2011
• 期刊: Biomolecular NMR assignments
• 影响因子: 0.9
• 作者: Reuther,Guido;Harris,Richard;Girvin,Mark;Leyh,ThomasS
• 通讯作者: Leyh,ThomasS

Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae.

• DOI: 10.1016/j.bmc.2009.12.050
• 发表时间: 2010-02
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Kudoh, Takashi;Park, Chan Sun;Lefurgy, Scott T.;Sun, Meihao;Michels, Theodore;Leyh, Thomas S.;Silverman, Richard B.
• 通讯作者: Silverman, Richard B.