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
- 来源:
- 关键词:Active SitesAnabolismAntibiotic ResistanceBacteriaBacterial InfectionsBindingBinding SitesBiochemicalBiochemistryBiological AssayCalorimetryCarbonCatalysisCell SurvivalCell membraneChemicalsChemistryCommunicable DiseasesComputer ModelsCryoelectron MicroscopyCrystallizationCysteineCytoplasmDataDevelopmentDiffusionDisease ResistanceDisulfidesEnvironmentEnzymesEquilibriumEscherichia coliEukaryotaFamilyFermentationFluorescenceFluorescence Resonance Energy TransferGene ExpressionGenetic TranscriptionGlucoseGlucose TransporterGlutathioneGlutathione DisulfideGlycolysisGram-Negative BacteriaGrowthHomeostasisHomologous ProteinIn SituIn VitroIntegral Membrane ProteinIntracellular MembranesLabelLipid BilayersLipidsMeasuresMediatingMembraneMetabolicMetabolic PathwayMetabolismMethodsMicrobiologyMolecularMolecular ConformationMonitorMutationOxidation-ReductionPacemakersPathway interactionsPhosphatidylglycerolsPhospholipidsPhosphoric Monoester HydrolasesProkaryotic CellsProtein ConformationProtein phosphataseProteinsRegulationReportingResolutionRoentgen RaysRoleSignal TransductionSiteStructureSurfaceTestingTitrationsVirulenceX-Ray Crystallographyaminoacid biosynthesisantimicrobialbacterial metabolismblood glucose regulationcell growthcell typecofactorcrosslinkdimergenetic approachglucose uptakeinorganic phosphateinsightmetabolomicsmicroorganismmutantnanodisknovelnovel therapeutic interventionparticlepathogenpreventresponseunnatural amino acidsvapor
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lei Zheng其他文献
Lei Zheng的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
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
骨骼合成代谢过程中的骨-脂肪相互作用
- 批准号:
10706006 - 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:
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
- 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:
10202896 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
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
- 批准号:
10531570 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10541847 - 财政年份:2019
- 资助金额:
$ 31.98万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10319573 - 财政年份:2019
- 资助金额:
$ 31.98万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10062790 - 财政年份:2019
- 资助金额:
$ 31.98万 - 项目类别:
Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
- 批准号:
DE170100628 - 财政年份:2017
- 资助金额:
$ 31.98万 - 项目类别:
Discovery Early Career Researcher Award