Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
批准号:
7564374
负责人:
KURT WARNCKE
金额:
$5.93万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-03-15 至 2008-06-30
关键词:
Active SitesAddressAminesAspirinBindingBiologicalBiologyCarbonCatalysisCell NucleusClassClassificationCobalaminCobaltCoenzymesComplexCoupledDNA Sequence RearrangementDNA biosynthesisDevelopmentElectron Nuclear Double ResonanceElectron Spin Resonance SpectroscopyElectronsEnzymesEthanolamine Ammonia-LyaseEventFree RadicalsFreezingFrequenciesFundingGenerationsGenetic RecombinationGoalsHourHydration statusHydrogenHydrogen BondingKineticsLasersLigandsLiquid substanceMeasurementMeasuresMediatingMetalsMethodsMethylmalonyl-CoA MutaseMolecularMolecular StructureNitrogenNon-Steroidal Anti-Inflammatory AgentsNuclearObject AttachmentOpticsOxidation-ReductionPhasePhysiologic pulsePowder dose formPreparationProcessProstaglandin-Endoperoxide SynthaseProtein DynamicsProteinsProtonsPulse takingQuantum MechanicsRangeReactionResearchRibonucleotide ReductaseRoentgen RaysRoleSolidSolventsSpectrum AnalysisSpin LabelsStructureSystemTechniquesTemperatureTestingTherapeuticTimeabsorptionaqueouschemical reactioncobamamidecofactorcorrincovalent bonddesignenzyme structureinsightmembermetalloenzymemigrationmolecular mechanicsmutantnovelphotolysisprogramsresearch studysolid statethree dimensional structure
中文摘要
利用缺电子自由基的极端反应性的酶
物种执行生物学中一些最困难的化学反应。这个
这些酶实现的区域和立体选择性打破了长期以来的观点
自由基反应是非特异性的。本课程包括以下内容:
核糖核苷酸还原酶,催化DNA中独特的第一步
生物合成、前列腺素H合成酶、阿司匹林和其他非类固醇的靶标
抗炎药物对S-腺苷蛋氨酸的依赖
酶,有600多个成员,催化广泛的自由基介导的
氧化还原反应和辅酶B12(腺苷钴胺)依赖
酶超家族,其成员催化代谢物共价键
重新安排。在这些化学上完全不同的
催化剂是一种金属辅助生成的缺电子有机自由基。
该引发剂自由基本身或通过次级自由基物种,
促进从底物中提取氢原子,形成以底物为基础的
自由基,打开一个新的反应通道,促进转化为
产品。一个悬而未决的问题是如何稳定激进分子对
快速复合,实现高产率的高效反应。澄清
蛋白质和辅因子如何引导自由基产生的基本原理,
稳定、蛋白质内自由基迁移和自由基重排将是
拟议研究的持续重点。辅酶B12依赖基因
酶,特别是乙醇胺解氨酶,已被选为
仔细检查。分子结构和动力学对酶的贡献
将利用脉冲电子顺磁技术来研究功能
低温陷阱中的共振和可见光/近红外吸收光谱
以及时间尺度从皮秒到几小时的时间分辨系统。
开发的基本见解和新方法将促进
其他生物中自由基中间体的鉴定和表征
反应,通知程序自由基反应性的设计,并协助
对抗有害的自由基过程的分子治疗努力。
英文摘要
Enzymes that harness the extreme reactivity of electron-deficient free radical
species carry out some of the most difficult chemical reactions in biology. The
regio- and stereo-selectivity achieved by these enzymes defies long-held ideas
that radical reactions are non-specific. This class includes the following:
ribonucleotide reductases, which catalyze the first unique step in DNA
biosynthesis, prostaglandin H-synthase, the target of aspirin and other nonsteroidal
anti-inflammatory drugs, the S-adenosylmethionine-dependent
enzymes, with over six-hundred members that catalyze a wide range of radicalmediated
redox reactions, and the coenzyme B12 (adenosylcobalamin)-dependent
enzyme superfamily, whose members catalyze metabolite covalent bond
rearrangements. The common primary step in these chemically-disparate
catalyses is metal-assisted generation of an electron-deficient organic radical.
This initiator radical, either by itself or through secondary radical species,
promotes hydrogen atom abstraction from the substrate to form a substratebased
radical, opening a new reaction channel that facilitates transformation to
the product. An outstanding issue is how the radical pair is stabilized against
rapid recombination to achieve productive reaction in high yield. Elucidating
the basic principles of how protein and cofactor guide radical generation,
stabilization, intra-protein radical migration, and radical rearrangement will be
sustained focuses of the proposed studies. The coenzyem B12-dependent
enzymes, and ethanolamine ammonia-lyase specifically, have been selected for
scrutiny. The contributions of molecular structure and dynamics to enzyme
function will be studied by using techniques of pulsed-electron paramagnetic
resonance and visible/near-infrared absorption spectroscopy, in cryotrapped
and time-resolved systems on time scales ranging from picoseconds to hours.
The fundamental insights and novel methods developed will promote
identification and characterization of radical intermediates in other biological
reactions, inform the design of programmed radical reactivity, and assist
molecular-therapeutic efforts to combat pernicious free radical processes.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Electron Paramagnetic Resonance Spectrometer
-
批准号:6582101
-
项目类别:
-
资助金额:$26.14万
-
财政年份:2003
-
负责人:KURT WARNCKE
-
依托单位:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
-
批准号:2703673
-
项目类别:
-
资助金额:$13.25万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:7653881
-
项目类别:
-
资助金额:$35.27万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:10701941
-
项目类别:
-
资助金额:$32.38万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
-
批准号:6489712
-
项目类别:
-
资助金额:$14.96万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:8918207
-
项目类别:
-
资助金额:$9.14万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:8266392
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:7163573
-
项目类别:
-
资助金额:$23.88万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:7803563
-
项目类别:
-
资助金额:$29.46万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
-
批准号:2856844
-
项目类别:
-
资助金额:$13.65万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:6581018
-
项目类别:
-
资助金额:$30.25万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:10254406
-
项目类别:
-
资助金额:$32.53万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:6699044
-
项目类别:
-
资助金额:$25.18万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:7002291
-
项目类别:
-
资助金额:$24.59万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
-
批准号:6138082
-
项目类别:
-
资助金额:$14.08万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
-
批准号:6342523
-
项目类别:
-
资助金额:$14.51万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:8064635
-
项目类别:
-
资助金额:$26.43万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:6835643
-
项目类别:
-
资助金额:$25.18万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis
-
批准号:10469587
-
项目类别:
-
资助金额:$32.46万
-
财政年份:1998
-
负责人:KURT WARNCKE
-
依托单位:
海外基金