The Mevalonate Pathway in Streptococcus

链球菌中的甲羟戊酸途径

• 批准号: 7082300
• 负责人: Thomas S. Leyh
• 金额: $ 56.03万
• 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/7082300
• 关键词: Streptococcus; active sites; allosteric site; antibiotics; enzymes; isozymes; ligands

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（由申请人提供）：肺炎链球菌（SP）每天夺走近4000人的生命，其中大多数是五岁以下的儿童。生物体的发展抗性机制的能力产生了能够耐受我们“防御”抗生素的菌株。该实验室最近发现，甲磷酸酯（DPM）是甲氯酸酯途径中的中间体，是SP甲基甲酸盐激酶（MK）的有效变构抑制剂（MK），并且不抑制人类同工酶。 Mevalonate途径对于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和靶标，为开发新的抗生素提供了机会，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丰富的媒体中的传染性SP。该建议在一个旨在探索和定义构成SP中大甲酸途径的酶的项目中整合了结构，功能和合成，并且在这样做为抗生素的设计和合成提供了基础。该程序将创建的信息具有相当大的基本科学价值。构成该途径的三种酶中的每种都是GHMP激酶蛋白超家族的成员，它们的生物医学相关性延伸至孤儿疾病和白内障的形成。我们已经确定了从SP的MK结构，并且迫在眉睫的DPM抑制复合物的结构是迫在眉睫的。这些结构定义了MK-target，并将揭示DPM结合如何破坏化学。我们还确定了SP的磷脂酸酯激酶（PMK）的三元复合物的结构，该复合物提出了有趣的机械问题，强调了PMK的独特和家族性结构元素。双磷酸化甲酸二氧化氢酯（DPM-DC）是一种引人入胜的酶，可通过碳分配过渡态脱羧DPM。我们将通过定义其过渡状态结构并监测配体和中间配合物的形成，从而为该机械类别创建高级催化范例，从而探索DPM-DC机制。