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）每天夺走近4000人的生命，其中大多数是孩子 低于五岁。生物体发展抗性机制的能力产生了能力 容忍我们“最后的防御”抗生素。这个实验室最近发现 Diphosphomevalonate（DPM）是甲氯酸酯途径中的中间体，是一种有效的变构抑制剂 SP甲硅酸盐激酶（MK），并且不抑制人类同工酶。 Mevalonate途径是 小鼠肺中生物的生存至关重要。 DPM和变构现场提供了铅化合物， 为开发新的抗生素提供机会的目标，可以帮助消除这种疾病。 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 SP在Rich Media中。该建议将旨在探索的项目集成了结构，功能和综合 并定义构成SP中甲谷酸途径的三种酶，并提供了一个基础 用于抗生素的设计和合成。该程序将创建的信息很大 基本科学价值。构成途径的三种酶中的每一个都是 GHMP激酶蛋白超家族，其生物医学相关性延伸到孤儿疾病和白内障 形成。我们已经确定了SP的MK结构，DPM抑制了MK的结构 与结合底物的复合物是迫在眉睫的。这些结构定义了MK-target，并将揭示DPM的方式 结合破坏了化学。我们还确定了磷脂酸酯三元复合物的结构 SP的激酶（PMK）提出了引人入胜的机械问题，强调了独特和 PMK的家族结构元素。双磷蛋白脱甲酸二氧基酶（DPM-DC）是一个引人入胜的 通过碳定位过渡状态将DPM脱羧的酶。我们将探索DPM-DC 通过定义其过渡状态结构并监测配体和中间体的形成来机制 为此机械类别创建高级催化范式的复合物。

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.