The Mevalonate Pathway in Streptococcus

肺炎链球菌（SP）每天夺走近4000人的生命，其中大多数是儿童 五岁以下的儿童。这种生物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。这个实验室最近发现， 二磷酸甲羟戊酸（diphosphomevalonate，DPO）是甲羟戊酸途径中的中间体，是一种有效的变构抑制剂， SP甲羟戊酸激酶（MK），并且它不抑制人同工酶。甲羟戊酸途径是 对小鼠肺中生物体的存活至关重要。它和变构位点提供了一种先导化合物， 这些目标为开发一种新抗生素提供了机会，这种抗生素可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感染性 SP在富媒体中。该提案将结构、功能和综合集成在一个项目中，旨在探索 并定义了SP中包含甲羟戊酸途径的三种酶，并在此过程中提供了一个基础 抗生素的设计和合成。该计划将创造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 阵我们测定了SP中MK的结构， 与结合底物的复合物即将发生。这些结构定义了MK-目标，并将揭示如何 结合破坏化学。我们还确定了磷酸甲羟戊酸的三元配合物的结构 激酶（PMK）从SP，这提出了有趣的机制问题，强调了独特的， PMK的家族结构要素。二磷酸甲羟戊酸脱羧酶（DPM-DC）是一种具有生物活性的 通过碳阳离子过渡态使β-淀粉酸脱羧的酶。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确定其机理 复合物，以创建一个先进的催化范例，为这个机械类。

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.