Salvage of the sulfur and carbon byproducts of S-adenosylmethionine metabolism in pathogenic bacteria
病原菌中S-腺苷甲硫氨酸代谢的硫和碳副产物的回收
基本信息
- 批准号:10610932
- 负责人:
- 金额:$ 15.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-13 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:5&apos-deoxyadenosineAddressAerobicAmino AcidsBacteriaBiological AvailabilityCancer Cell GrowthCarbonCellsConsumptionDNA MethylationEnvironmentEnzymesEthylenesExposure toGene ExpressionGenesGoalsGrowthHealthHumanIn VitroInfectionIntestinesIslandLaboratoriesLiver CirrhosisLower OrganismMetabolicMetabolic PathwayMetabolismMethionineMethodsMutagenesisOrganismPathogenesisPathogenicityPathologyPathway interactionsPersonsPhysiologicalPolyaminesPrevalenceProcessProtein MethylationProteomicsQuantitative Reverse Transcriptase PCRRadiolabeledReactionRegulatory ElementResolutionRoleS-AdenosylhomocysteineS-AdenosylmethionineShunt DeviceSiderophoresSiteStructural GenesSulfateSulfurTestingTherapeuticTherapeutic AgentsTranslatingWorkanalogcostdesignexperimental studyfeedingfitnessgenetic regulatory proteinhomoserine lactonein vivoinhibitorinterestmutantnovelpathogenpathogenic Escherichia colipathogenic bacteriaquorum sensingshunt pathwaytranscriptomics
项目摘要
Project Summary
Biologically available sulfur is essential for the synthesis of methionine (Met) and its derivative, S-adenosyl-L-
methionine (SAM). SAM is used for diverse metabolic purposes, serving primarily as a methyl donor for DNA
and protein methylation, as a 5’-deoxyadenosyl radical donor for radical-SAM reactions, as an aminopropyl donor
for polyamine synthesis and volved in the synthesis of acyl-homoserine lactone quorum sensing molecules in
bacteria. As a consequence of this metabolism, a dead-end, sulfur-containing byproduct, 5’-methylthioadenosine
(MTA) is formed. MTA is a product inhibitor of polyamine synthesis and MTA accumulation is thought to be toxic.
Since the assimilation of inorganic sulfur is energetically costly and many organisms encounter sulfur-poor
environments, maintaining or salvaging appropriate cellular organic sulfur pools is critical. Moreover, disruption
or reduced functioning of methionine salvage pathways (MSPs) has many health-related consequences
including influences on cancer cell growth and liver cirrhosis; intermediates of the pathway have also been shown
to influence apoptopic processes, while analogs of these intermediates are promising therapeutic agents. Newly
discovered MTA pathways from our laboratory, the DHAP-ethylene and methanethiol shunts, were recently
described, the genes of which appear to be widespread and selectively found among several pathogenic species.
Nonpathogenic species from these genera do not contain these genes. Thus, the hypothesis is that the shunt
genes/enzymes hold some special significance to metabolism of these pathogenic species. Moreover, the same
novel genes and enzymes were recently found to participate in radical SAM reactions to generate and metabolize
5’-deoxyadenosine (5dAdo), a structurally similar byproduct to MTA, which could potentially be recycled for
carbon salvage. The long-term goal will thus be to determine the role and physiological significance of the
DHAP/MTA/5dAdo pathways for sulfur and carbon salvage, and the potential of these pathways to influence the
successful metabolism of extraintestinal pathogenic Escherichia coli (ExPEC), including uropathogenic (UPEC)
strains which contain these genes on a specific pathogenesis island. A specific aim (Aim 1) will be to determine
the precise role of these genes and encoded enzymes and resolve further metabolic steps in sulfur/carbon
salvage via whole cell feeding experiments using radio-labeled (14C) and 13C MTA and 5dAdo metabolites in wild
type and mutant strains. These in vivo studies will be supplemented by in vitro analyses with specific enzymes.
The second aim (Aim 2) will involve resolving how these genes are genetically regulated, an important facet of
sulfur/carbon salvage in these organisms. Resolution of the specific aims of this project have considerable health
relevance as ExPEC/UPEC strains cause major health problems and infect millions of people. It is conceivable
that the identification and resolution of a specific sulfur/carbon salvage pathway essential for
pathogenesis/fitness will open the way to design specific targets to inhibit infections caused by these organisms.
项目总结
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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Justin Andrew North其他文献
Justin Andrew North的其他文献
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{{ truncateString('Justin Andrew North', 18)}}的其他基金
Salvage of the sulfur and carbon byproducts of S-adenosylmethionine metabolism in pathogenic bacteria
病原菌中S-腺苷甲硫氨酸代谢的硫和碳副产物的回收
- 批准号:
10399586 - 财政年份:2020
- 资助金额:
$ 15.6万 - 项目类别:
Characterization of novel sulfur salvage mechanisms in Rodospirillum rubrum
红色红螺菌新型硫回收机制的表征
- 批准号:
8912286 - 财政年份:2014
- 资助金额:
$ 15.6万 - 项目类别:
Characterization of novel sulfur salvage mechanisms in Rodospirillum rubrum
红色红螺菌新型硫回收机制的表征
- 批准号:
8781601 - 财政年份:2014
- 资助金额:
$ 15.6万 - 项目类别:
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