Biochemical Mechanisms of Polyphosphate in Metabolism

多磷酸盐代谢的生化机制

基本信息

批准号：
6849215
负责人：
ARTHUR KORNBERG
金额：
$ 26.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2006-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Inorganic polyphosphate (poly P), a polymer of hundreds of phosphate residues linked by high-energy bonds, is found in every cell in Nature-bacteria, fungi, plants and animals. Among poiy P functions are: kinase donor to glucose and nucleoside diphosphates, phosphate (P1) reservoir, divalent metal (Ca2+, Mg2+, Mn2+) chelator and component of a membrane complex in bacterial transformation. Our recent studies have disclosed three major roles: 1) "alarmone" in response to stresses and deficiencies, 2) adaptations for survival in the stationary phase and 3) virulence in some pathogens. Thus, poly P has a variety of functions depending on the cell and circumstances. The multiplicity of functions and the plasticity of microbial organisms has complicated the search for the biochemical mechanisms responsible for each action. The proposed research will focus on mechanisms of metabolic regulation. Based on promising preliminary studies, we intend to pursue two major lines: 1) Regulation of protein synthesis and turnover by the supply of amino acids by biosynthesis and protein turnover, and 2) Operations of phosphate uptake and efflux and concomitant divalent metal ion transport. In addition, we will be mindful of control of in vitro transcription of genes known to be activated by poly P in vivo and a possible role for poly P as a donor for protein kinases. The widespread conservation of the enzyme, poly P kinase (PPK), responsible for poiy P synthesis in bacteria, including many of the major pathogens, has led us to knockout ppk in several of these pathogens. In Pseudomonas aeruginosa poly P is essential for motility, quorum sensing, bioflim formation and virulence in mice. We expect that the proposed biochemical studies will reveal mechanisms that will assist in the current search for antimicrobial drugs aimed at PPK as a target. The research may also provide clues to the biosynthesis and metabolism of poly P in eukaryotes about which little is known. In view of the ubiquity of poly P in animal cells and subcellular organelles (particularly nuclei), it seems likely that poly P serves multiple functions in human metabolism that affect growth, differentiation and disease.

描述（由申请人提供）：无机聚磷酸盐（poly P），一种发现了数百个通过高能键连接的磷酸残基的聚合物存在于自然界的每一个细胞中——细菌、真菌、植物和动物。其中聚P 功能是：葡萄糖和核苷二磷酸、磷酸的激酶供体 (P1) 储库、二价金属（Ca2+、Mg2+、Mn2+）螯合剂和组分细菌转化中的膜复合物。我们最近的研究揭示了三个主要作用：1）“警报”以应对压力和缺陷，2）稳定期生存的适应和 3) 某些病毒的毒力病原体。因此，poly P 具有多种功能，具体取决于细胞和情况。微生物的功能多样性和可塑性生物体使寻找造成这种现象的生化机制变得更加复杂。对于每个动作。拟议的研究将集中于代谢机制规定。基于有希望的初步研究，我们打算追求两条主线：1) 通过提供氨基酸来调节蛋白质合成和周转生物合成和蛋白质周转，以及 2) 磷酸盐吸收和运作外排和伴随的二价金属离子转运。此外，我们还会留意已知体内多聚磷激活的基因的体外转录控制以及聚 P 作为蛋白激酶供体的可能作用。多聚 P 激酶 (PPK) 的广泛保守性负责细菌（包括许多主要病原体）中的聚磷合成使我们敲除其中几种病原体中的 ppk。铜绿假单胞菌中的聚P 对于运动、群体感应、生物膜形成和毒力至关重要老鼠。我们期望拟议的生化研究将揭示机制这将有助于当前寻找针对 PPK 的抗菌药物一个目标。该研究还可能为生物合成和真核生物中多聚磷的代谢知之甚少。鉴于聚 P 在动物细胞和亚细胞器（特别是核），看来聚 P 在人类中具有多种功能影响生长、分化和疾病的新陈代谢。