Enzyme Catalysis of Toluene Degradation and Unusual DNA Photoproduct Repair
酶催化甲苯降解和异常 DNA 光产物修复
基本信息
- 批准号:8117523
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-01 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAdoptedAmino AcidsAnthrax diseaseBacillus anthracisBacteriaBacterial SporesBiochemical ProcessBiological ProcessBotulismCarbonCatalysisChemistryClostridium botulinumCoenzymesCoupledCrystallographyDNADNA RepairDNA Repair EnzymesDNA Repair PathwayDNA biosynthesisDNA photoproductsDNA-Protein InteractionDiseaseEndospore-Forming BacteriaEnvironmentEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesExcisionFermentationFood PoisoningFree RadicalsGenerationsGerminationGoalsHumanHydrocarbonsIsotopesKineticsMeasurableMediatingMethodsMicrobeMutagenesisNamesNatureOrganic ChemistryOxidation-ReductionPhaseProteinsReactionReproduction sporesResearchResearch Project GrantsS-AdenosylmethionineSnoringSourceSterilizationStructureSurveysThymineTolueneanalogbasechemical kineticscrosslinkenzyme mechanismin vivoinhibitor/antagonistmedical schoolsnovelpollutantpreventpublic health relevancerepairedspore photoproduct lyasesugartoolultraviolet damageultraviolet irradiation
项目摘要
Enzynnes utilize organic radicals to catalyze a variety of important nnetabolic reactions. The overall goal of
this research is to delineate the mechanistic details of radical generation and control by these enzymes. This
research in the ROO phase will focus on a DNA repair enzyme named spore photoproduct lyase (SPL). SPL
utilizes S-adenosylmethionine (SAM) coupled by a unique [4Fe-4S] cluster to generate the reactive organic
radicals to repair the unique T-T crosslink 5-thyminyl-5, 6-dihydrothymine (commonly called spore
photoproduct, SP) formed upon UV irradiation.
SPL exists in the spores of bacteria such as B. subtilis and B. anthracis. It adopts a "direct reverse" strategy
to repair SP, meaning that the UV damage is quickly reversed with neither removal nor replacement of the
damaged thymine bases. It thus represents a unique DNA repair pathway in Nature. In addition, the efficient
DNA repair catalyzed by SPL makes UV irradiation no longer lethal to the spore-forming bacteria. To
understand the SPL mediated DNA repair reaction, chemical, kinetic, spectroscopic, and mutagenic methods
will be employed. The objectives include: investigating the SPL activity using substrates with a wide range of
DNA secondary structures, probing the reaction mechanism by SP analogues (mechanism-based enzyme
inhibitors), and examining the kinetic isotope effects and reaction reversibility. In addition, the redox potential of the [4Fe-4S] cluster will be determined and the influence of SAIV! and key amino acids to the redox potential will be investigated.
Understanding the enzyme mechanism will help us identify potential SPL inhibitors. As SPL is the key enzyme to repair the UV damage in endospore-forming bacteria, inhibiting its activity in vivo will prevent the bacteria from fixing these damages at the germination phase. In combination with the SPL inhibitor, UV irradiation will regain its power as a cheap and convenient tool for sterilization purpose.
酶利用有机自由基催化多种重要的非代谢反应。的总目标
本研究旨在阐明这些酶的自由基产生和控制机制的细节。这
ROO阶段的研究将集中在一种名为孢子光产物裂解酶(SPL)的DNA修复酶上。SPL
利用由独特的[4Fe-4S]簇偶联的S-腺苷甲硫氨酸(SAM)产生反应性有机
自由基来修复独特的T-T交联5-胸腺嘧啶-5,6-二氢胸腺嘧啶(通常称为孢子
光产物,SP)。
SPL存在于细菌如B的孢子中。枯草芽孢杆菌和B.炭疽病它采取“直接反向”策略
修复SP,这意味着紫外线的损害是迅速逆转,既不删除或更换的
受损的胸腺嘧啶碱基因此,它代表了自然界中独特的DNA修复途径。此外,高效
SPL催化的DNA修复使紫外线照射对产芽孢细菌不再致命。到
了解SPL介导的DNA修复反应,化学,动力学,光谱和诱变方法
将被雇用。目的包括:调查SPL活动使用的基板具有广泛的
DNA二级结构,通过SP类似物探测反应机理(基于机理的酶
抑制剂),并检查动力学同位素效应和反应可逆性。此外,氧化还原电位的[4Fe-4S]集群将被确定和SAIV!和关键氨基酸的氧化还原电位将进行研究。
了解酶的机制将有助于我们识别潜在的SPL抑制剂。由于SPL是内孢子形成细菌中修复紫外线损伤的关键酶,因此在体内抑制其活性将防止细菌在萌发阶段修复这些损伤。结合SPL抑制剂,紫外线照射将恢复其作为一种廉价和方便的工具用于灭菌目的的权力。
项目成果
期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reactivity of damaged pyrimidines: DNA cleavage via hemiaminal formation at the C4 positions of the saturated thymine of spore photoproduct and dihydrouridine.
- DOI:10.1021/ja505407p
- 发表时间:2014-09-17
- 期刊:
- 影响因子:15
- 作者:Lin G;Jian Y;Dria KJ;Long EC;Li L
- 通讯作者:Li L
Correction to Mechanistic Studies of the Spore Photoproduct Lyase via a Single Cysteine Mutation.
通过单一半胱氨酸突变校正孢子光产物裂解酶的机制研究。
- DOI:10.1021/bi301546f
- 发表时间:2012
- 期刊:
- 影响因子:2.9
- 作者:Yang,Linlin;Lin,Gengjie;Nelson,RenaeS;Jian,Yajun;Telser,Joshua;Li,Lei
- 通讯作者:Li,Lei
Oxidation and reduction of the 5-(2'-deoxyuridinyl)methyl radical.
- DOI:10.1002/anie.201209454
- 发表时间:2013-05-17
- 期刊:
- 影响因子:16.6
- 作者:Lin, Gengjie;Li, Lei
- 通讯作者:Li, Lei
Examining the base stacking interaction in a dinucleotide context via reversible cyclobutane dimer analogue formation under UV irradiation.
通过紫外线照射下可逆的环丁烷二聚体类似物的形成来检查二核苷酸环境中的碱基堆积相互作用。
- DOI:10.1039/c3ra41702f
- 发表时间:2013
- 期刊:
- 影响因子:3.9
- 作者:Liu,Degang;Li,Lei
- 通讯作者:Li,Lei
Mechanistic studies of the radical SAM enzyme spore photoproduct lyase (SPL).
- DOI:10.1016/j.bbapap.2011.11.008
- 发表时间:2012-11
- 期刊:
- 影响因子:3.2
- 作者:Li, Lei
- 通讯作者:Li, Lei
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{{ truncateString('Lei Li', 18)}}的其他基金
Expedite Enzymatic Assembly of Glycans via DNA (de)Hybridization-Enabled Catch-and-Release
通过 DNA(去)杂交捕获和释放加速聚糖的酶促组装
- 批准号:
10648697 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Center for the Investigation of Factor VIII Inhibitors and Glycosylation
因子 VIII 抑制剂和糖基化研究中心
- 批准号:
10406318 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Center for the Investigation of Factor VIII Inhibitors and Glycosylation
因子 VIII 抑制剂和糖基化研究中心
- 批准号:
10227911 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Facile Synthesis of O-Glycans and O-Glycopeptides
O-聚糖和 O-糖肽的简便合成
- 批准号:
8985647 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
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