Enzymatic Hydrolysis of Organophosphate Esters
有机磷酸酯的酶水解
基本信息
- 批准号:9235651
- 负责人:
- 金额:$ 27.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAgricultureAmino Acid SequenceBacteriaBindingBiologicalChemical Warfare AgentsChemicalsComplementCrystallizationDetectionDrug Metabolic DetoxicationEnzyme Inhibitor DrugsEnzymesEstersEventExhibitsFlame RetardantsHouseholdHydrolysisInsecticidesIsotopesKineticsLabelLaboratoriesLibrariesLigandsMeasurementMethodsMonitorMutagenesisOrganophosphatesOxygenPesticidesPhosphoric Triester HydrolasesPhosphorusPlasticizersProceduresProdrugsPropertyPseudomonasReactionResearchResolutionSeriesShapesSite-Directed MutagenesisSomanStructureToxic effectVariantVirus DiseasesX ray diffraction analysisX-Ray Diffractioncatalystchemical reactioncombinatorialdesignenzyme mechanismexperimental studyinhibitor/antagonistmutantnerve agentnovelscreeningthree dimensional structure
项目摘要
The primary objective for the research described in this proposal is the elucidation of the
chemical reaction mechanism and three-dimensional structure of a novel phosphotriesterase recently
identified from the bacterium Spingobium sp. strain TCM1 (Sb-PTE). The high toxicity of many
organophosphate triesters has been exploited as the active component in many commercial
agricultural and household insecticides and as ultra-potent chemical warfare agents. Other, less toxic,
organophosphate compounds have been widely utilized as flame retardants, plasticizers, and as
prodrugs for viral infections. The catalytic properties and three-dimensional structure of the wild-
type Sb-PTE are significantly different from those exhibited by the phosphotriesterase from
Pseudomonas diminuta (Pd-PTE) or any other enzyme identified to date. We propose to utilize this
enzyme as a template for the design and creation of new biological catalysts that can be exploited for
the detection, destruction, and detoxification of toxic organophosphate nerve agents that are currently
being used as agricultural and household insecticides, plasticizers, and chemical warfare agents. The
chemical mechanism for this enzyme will be elucidated by determining the stereochemical course of
the reaction with chiral substrates and by monitoring the fate of 18-oxygen labels in the substrate and
enzyme. These experiments will be complemented by measurement of heavy atom isotope effects,
determination of the substrate/activity profile, and the identification of potent enzyme inhibitors. In
preliminary experiments we have succeeded in the crystallization of Sb-PTE and determination of its
three dimensional structure by X-ray diffraction methods. Further structures will be pursued in a
focused attempt to determine the mode of substrate binding within the active site of this enzyme.
These structures will be utilized as a guide for the design and creation of novel enzyme variants with
unique substrate profiles. Rational and combinatorial libraries of mutant enzymes will be constructed
and those variants with enhanced catalytic proficiency for the hydrolysis of toxic organophosphates
will be identified through unique screening and selection procedures. The changes in the amino acid
sequence of the Sb-PTE mutants will be correlated with enhancements in the catalytic properties and
alterations in the structure within the active site.
本提案中所描述的研究的主要目的是阐明
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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Frank M. Raushel其他文献
Catalytic detoxification
催化解毒
- DOI:
10.1038/469310a - 发表时间:
2011-01-19 - 期刊:
- 影响因子:48.500
- 作者:
Frank M. Raushel - 通讯作者:
Frank M. Raushel
The use of phosphotriesterase in the synthesis of enantiomerically pure ProTide prodrugs
磷酸三酯酶在合成对映体纯的前药ProTide中的应用
- DOI:
10.1016/j.cbi.2025.111597 - 发表时间:
2025-09-05 - 期刊:
- 影响因子:5.400
- 作者:
Andrew N. Bigley;Frank M. Raushel - 通讯作者:
Frank M. Raushel
Frank M. Raushel的其他文献
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{{ truncateString('Frank M. Raushel', 18)}}的其他基金
The Discovery of Novel Metabolic Pathways for the Biosynthesis and Degradation of Complex Carbohydrates within the Human Gut Microbiome
人类肠道微生物组内复杂碳水化合物生物合成和降解的新代谢途径的发现
- 批准号:
10323657 - 财政年份:2021
- 资助金额:
$ 27.93万 - 项目类别:
The Discovery of Novel Metabolic Pathways for the Biosynthesis and Degradation of Complex Carbohydrates within the Human Gut Microbiome
人类肠道微生物组内复杂碳水化合物生物合成和降解的新代谢途径的发现
- 批准号:
10557076 - 财政年份:2021
- 资助金额:
$ 27.93万 - 项目类别:
The Discovery of Novel Metabolic Pathways for the Biosynthesis and Degradation of Complex Carbohydrates within the Human Gut Microbiome
人类肠道微生物组内复杂碳水化合物生物合成和降解的新代谢途径的发现
- 批准号:
10084621 - 财政年份:2021
- 资助金额:
$ 27.93万 - 项目类别:
Novel Biochemical Pathways for the Metabolism of Carbohydrates in the Human gut Micriobiome
人类肠道微生物组中碳水化合物代谢的新生化途径
- 批准号:
10063528 - 财政年份:2017
- 资助金额:
$ 27.93万 - 项目类别:
Deciphering Enzyme Specificity: Amidohydrolase Superfamily
破译酶的特异性:酰胺水解酶超家族
- 批准号:
7743893 - 财政年份:2009
- 资助金额:
$ 27.93万 - 项目类别:
Enzymic Detoxification for Organophosphate Nerve Agents
有机磷神经毒剂的酶解毒
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8114985 - 财政年份:2003
- 资助金额:
$ 27.93万 - 项目类别:
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