Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments
多种过渡金属和自由基化学使细菌在限制性环境中生产 2-脱氧核糖核苷酸
基本信息
- 批准号:10165753
- 负责人:
- 金额:$ 37.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAerococcusAmino AcidsAmmoniumAntibioticsBacteriaCatalysisCatalytic DomainCationsCellsChargeChemistryComplexCysteineDNADNA RepairDNA biosynthesisDataDeoxyribonucleotidesDependenceDiseaseElectronsEnsureEnvironmentEnzymesEvolutionFailureFlavobacteriaFlavoproteinsFree RadicalsGene Expression ProfilingGenerationsGenesGrowthHospitalsHumanHydrophobicityImmune responseIn VitroInfectionIronLigandsLightLysineManganeseMetalsNucleotidesOrganismOxidantsOxidesPharyngeal structurePhysiologicalPositioning AttributeProcessProductionPropertyProteinsReactionReportingRibonucleotide ReductaseRoleScarlet FeverSiteStreptococcus pyogenesStructureSuperoxidesSystemTissuesTransition ElementsWorkX-Ray Crystallographybasecofactorcomplex IVdehydroxylationdeprivationdesigndrug discoveryin vivomembermicrobialopportunistic pathogenoxidationpathogenpathogenic bacteriapathogenic microbe
项目摘要
Project Summary/Abstract
All organisms obtain the deoxynucleotide substrates for DNA synthesis and repair by the action of an enzyme
known as ribonucleotide reductase (RNR). The several known types of RNRs, which have been divided into
classes I, II, and III, differ in the transition-metal and free-radical chemistry that they use to initiate their
common, challenging reduction/dehydroxylation reaction. Recent studies have shown that many bacteria that
infect and cause disease in humans use class I RNRs that differ markedly from the human class I, subclass a
enzyme. Some of these microbial RNRs (subclasses b and d) use manganese instead of iron in what is
thought to be an adaptation to iron deprivation caused by the human immune response, and others use both
metals (subclass c). We just discovered that a new type of RNR from the causative agent of strep throat and
scarlet fever may have fully escaped the usual dependence on transition metals by using a previously
unknown type of stable amino acid radical, thus founding subclass e. This project will reveal precisely how the
members of three new subclasses of class I RNRs (including d and e) that were recently identified in
pathogenic bacteria acquire their catalytic activity and initiate nucleotide reduction. The very different initiation
chemistry used by the pathogens' enzymes offers opportunities for their selective inhibition by antibiotics. This
project will provide the conceptual underpinnings for such drug discovery efforts and will shed light on the ways
in which pathogenic microbes have adapted to cope with their hosts' hostile immune response.
项目总结/摘要
所有的生物体都能通过酶的作用获得脱氧核苷酸作为DNA合成和修复的底物
称为核糖核苷酸还原酶(RNR)。几种已知类型的RNR,已被分为
I类、II类和III类的不同之处在于它们用来引发它们的过渡金属和自由基化学反应。
常见的具有挑战性的还原/脱羟基反应。最近的研究表明,
使用与人类I类a亚类显著不同的I类RNR感染人类并引起疾病
酵素这些微生物RNR中的一些(亚类B和d)在所述微生物RNR中使用锰而不是铁。
被认为是对人体免疫反应引起的缺铁的一种适应,而其他人则两者兼而有之。
金属(c类)。我们刚刚发现一种新型的RNR来自链球菌性咽喉炎的病原体,
猩红热可能完全逃脱了通常对过渡金属的依赖,
未知类型的稳定氨基酸基团,从而建立e亚类。这个项目将揭示如何准确地
I类RNR的三个新子类(包括d和e)的成员,最近在
病原菌获得它们的催化活性并启动核苷酸还原。非常不同的启蒙
病原体的酶所使用的化学物质为抗生素选择性抑制它们提供了机会。这
该项目将为此类药物发现工作提供概念基础,并揭示如何
病原微生物已经适应科普宿主的敌对免疫反应。
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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JOSEPH M BOLLINGER其他文献
JOSEPH M BOLLINGER的其他文献
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{{ truncateString('JOSEPH M BOLLINGER', 18)}}的其他基金
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:
10647843 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:
10428624 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:
10035218 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:
10208910 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments
多种过渡金属和自由基化学使细菌在限制性环境中生产 2-脱氧核糖核苷酸
- 批准号:
10417125 - 财政年份:2019
- 资助金额:
$ 37.74万 - 项目类别:
Mechanisms and Reprogramming of Iron/2-Oxoglutarate Desaturases and Oxacyclases
铁/2-氧戊二酸去饱和酶和氧杂环酶的机制和重编程
- 批准号:
9262989 - 财政年份:2016
- 资助金额:
$ 37.74万 - 项目类别:
Mechanisms and Reprogramming of Iron/2-Oxoglutarate Desaturases and Oxacyclases
铁/2-氧戊二酸去饱和酶和氧杂环酶的机制和重编程
- 批准号:
9084003 - 财政年份:2016
- 资助金额:
$ 37.74万 - 项目类别:
Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases
安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制
- 批准号:
9139962 - 财政年份:2015
- 资助金额:
$ 37.74万 - 项目类别:
Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases
安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制
- 批准号:
8965103 - 财政年份:2015
- 资助金额:
$ 37.74万 - 项目类别:
Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases
安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制
- 批准号:
9309007 - 财政年份:2015
- 资助金额:
$ 37.74万 - 项目类别: