Structure and function of a metabolic pacemaker in bacterial cell membrane

细菌细胞膜代谢起搏器的结构和功能

基本信息

  • 批准号:
    10652472
  • 负责人:
  • 金额:
    $ 31.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Abstract Glycolysis constitutes one of the most important metabolic pathways conserved in both eukaryotes and prokaryotes. In the pathway, glucose is broken down to form small 3-carbon phosphate metabolites essential for cell growth and survival. In microorganisms, properly maintaining glycolysis is important for the development of bacterial infection and virulence and antibiotic resistance. In this project, we aim to study the structure and function of phosphatidylglycerol phosphatase PgpA to elucidate a novel regulatory mechanism of glycolysis in bacterium. PgpA is an integral membrane protein ubiquitously found in Gram-negative bacterium. We found that PgpA functions as a moonlighting enzyme; i.e. PgpA is not only involved in phospholipid biosynthesis but also acts as an essential metabolic regulator by hydrolyzing the key 3-carbon phosphate glycolytic metabolites in E. coli. Mutational inactivation of PgpA in E. coli greatly facilitates bacterial metabolism and growth. We have also identified a novel redox-regulatory mechanism of PgpA, which is important to maintain bacterial metabolic homeostasis. Our findings raise the hypothesis for a redox-mediated regulatory mechanism in which PgpA regulates bacterial glycolysis by controlling glutathione-mediated redox balance based on external and internal metabolic signals. This regulatory mechanism is novel and has not yet been reported in any cell type. To further understand this regulatory mechanism, we will study how PgpA controls bacterial glucose uptake and regulate glycolytic activity using a combination of biochemistry, microbiology, and metabolomic approaches.To understand how PgpA regulates intracellular redox balance, we will examine glutathione biosynthesis and monitor redox changes on the membrane surface of PgpA to demonstrate how PgpA uses an integrative “Ying- Yang” mechanism to achieve both metabolic homeostasis and redox balance. We also found the redox-mediated regulation of PgpA is mediated by dimeric disulfide crosslinking within PgpA dimer. To gain structural insights into this novel redox-regulated catalytic mechanism, we will study the catalytic activity of PgpA and co-factor Mg2+ binding in response to redox changes in vitro using biochemical assays. We will also study this molecular mechanism using FRET to demonstrate how dimeric crosslinking alters protein conformation to allosterically change the active site conformation in order to control the PgpA catalysis. Since no structure is available in the PgpA family, we will determine the structures of PgpA in two distinct redox (active/inactivated) states using the X-ray crystallography and single-particle cryoEM approaches to establish a structural basis for the redox- regulated catalytic mechanism of PgpA. This mechanism is conserved in many Gram-negative pathogens. Our studies will reveal an important mechanism to understand metabolic regulation in microorganisms.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Lei Zheng其他文献

Lei Zheng的其他文献

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{{ truncateString('Lei Zheng', 18)}}的其他基金

Integration of stromal targeting agents with immune checkpoint therapy
基质靶向剂与免疫检查点疗法的整合
  • 批准号:
    10408084
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Structure and function of a metabolic pacemaker in bacterial cell membrane
细菌细胞膜代谢起搏器的结构和功能
  • 批准号:
    10280369
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Structure and function of a metabolic pacemaker in bacterial cell membrane
细菌细胞膜代谢起搏器的结构和功能
  • 批准号:
    10457395
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Integration of stromal targeting agents with immune checkpoint therapy
基质靶向剂与免疫检查点疗法的整合
  • 批准号:
    10661808
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Structure and function of a metabolic pacemaker in bacterial cell membrane
细菌细胞膜代谢起搏器的结构和功能
  • 批准号:
    10796719
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Annexin A2 as a mediator of pancreatic cancer metastases
膜联蛋白 A2 作为胰腺癌转移的介质
  • 批准号:
    8579467
  • 财政年份:
    2013
  • 资助金额:
    $ 31.98万
  • 项目类别:
Annexin A2 as a mediator of pancreatic cancer metastases
膜联蛋白 A2 作为胰腺癌转移的介质
  • 批准号:
    8712421
  • 财政年份:
    2013
  • 资助金额:
    $ 31.98万
  • 项目类别:
Interrogate the interaction between tumor cells and nerves in the tumor microenvironment of pancreatic cancer
探究胰腺癌肿瘤微环境中肿瘤细胞与神经之间的相互作用
  • 批准号:
    9764752
  • 财政年份:
    2013
  • 资助金额:
    $ 31.98万
  • 项目类别:
Interrogate the interaction between tumor cells and nerves in the tumor microenvironment of pancreatic cancer
探究胰腺癌肿瘤微环境中肿瘤细胞与神经之间的相互作用
  • 批准号:
    10578764
  • 财政年份:
    2013
  • 资助金额:
    $ 31.98万
  • 项目类别:
Interrogate the interaction between tumor cells and nerves in the tumor microenvironment of pancreatic cancer
探究胰腺癌肿瘤微环境中肿瘤细胞与神经之间的相互作用
  • 批准号:
    10358637
  • 财政年份:
    2013
  • 资助金额:
    $ 31.98万
  • 项目类别:

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Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
    10590611
  • 财政年份:
    2022
  • 资助金额:
    $ 31.98万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
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  • 批准号:
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  • 财政年份:
    2022
  • 资助金额:
    $ 31.98万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
    10368975
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
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  • 批准号:
    10365254
  • 财政年份:
    2021
  • 资助金额:
    $ 31.98万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
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  • 财政年份:
    2021
  • 资助金额:
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BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
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Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
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    DE170100628
  • 财政年份:
    2017
  • 资助金额:
    $ 31.98万
  • 项目类别:
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