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
基本信息
- 批准号:9262989
- 负责人:
- 金额:$ 25.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-15 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAlcoholsAmino Acid SubstitutionAnabolismAnestheticsAntibioticsArginineBacteriaBindingBiochemical PathwayCarbonCell NucleusCellsClinicalComplexCouplingCrystallographyCyclizationDioxygenasesDirected Molecular EvolutionDiseaseDrug CompoundingDrug DesignElectron Spin Resonance SpectroscopyEngineeringEnzymesEpigenetic ProcessEpoxy CompoundsEscherichia coliEventGenetic RecombinationGenetic TranscriptionGeometryGlutamatesGlutaratesGuanidinesHalogensHumanHydrogenHydrogen BondingHydroxylationIn VitroIonsIronKineticsLibrariesLifeLigandsLocationMapsMetabolismMetalsMethodologyMethodsMixed Function OxygenasesMutagenesisNatural Product DrugOutcomeOxygenOxygenasesPathway interactionsPharmaceutical PreparationsPositioning AttributeProcessProductionReactionRegulationResidual stateRoleScopolamineSiteSoilStructureTestingVanadylVariantWorkX-Ray Crystallographyadductalpha ketoglutaratecatalystcofactorcombinatorialcomputer studiesdehydrogenationdesaturaseexperimental studyextradiol dioxygenasefischerindolefrontierhalogenationhydroxyl groupin vivoinnovationinsightiron nitrosylmicrobialnovel therapeuticsplant fungipreventscreeningtoolvector
项目摘要
Human iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) dioxygenases hydroxylate
unactivated aliphatic carbon centers in reactions that are fundamentally important to
central life processes (e.g., metabolism and its regulation, transcription, epigenetic
inheritance) and relevant to several diseases. Plant, fungi, and bacteria have diversified
the Fe/2OG-oxygenase platform for a bewildering array of oxidative transformations that
include halogenations, cyclizations, dehydrogenations and stereoinversions of aliphatic
carbon centers. As the biosynthetic machinery generating a large number of important
natural-product drugs are replete with such Fe/2OG oxygenases, the ability to reprogram
them by either rational or directed-evolution approaches would enable microbial/enzy-
matic production of novel drug compounds. In this project, we will use in vivo and in
vitro selection methods to engineer outcome-altered variants of Fe/2OG oxygenases on
pathways to antibiotic and anesthetic drugs. Our extensively validated kinetic and
spectroscopic approaches to structural and functional analysis of these enzymes will be
applied in combination with two new, innovative structural methods to rationalize the
reprogramming in precise structural and mechanistic terms. The project will thus provide
both enzymes for production of new potential drugs and mechanistic insight to enable
more rational reprogramming of these and other Fe/2OG oxygenases.
人铁(II)和2-(氧代)戊二酸依赖性(Fe/2 OG)双加氧酶羟基化
在反应中未活化的脂肪族碳中心,这对
中心生命过程(例如,代谢及其调控,转录,表观遗传
遗传),并与多种疾病有关。植物、真菌和细菌已经多样化
Fe/2 OG-加氧酶平台用于一系列令人困惑的氧化转化,
包括脂肪族化合物卤化、环化、双取代和立体转化
碳中心作为生物合成机器,
天然产物药物充满了这样的Fe/2 OG加氧酶,重新编程的能力,
通过理性或定向进化的方法,它们将使微生物/酶
新型药物化合物的自动生产。在这个项目中,我们将使用在体内和在
体外选择方法来工程化Fe/2 OG加氧酶的结果改变的变体,
抗生素和麻醉药的途径。我们经过广泛验证的动力学和
光谱方法的结构和功能分析这些酶将是
结合两种新的、创新的结构方法,
在精确的结构和机制方面重新编程。该项目将提供
既有用于生产新的潜在药物的酶,
这些和其他Fe/2 OG加氧酶的更合理的重编程。
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:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 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:
10165753 - 财政年份:2019
- 资助金额:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 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:
$ 25.94万 - 项目类别:
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