Structure, Function and Diversity in the Bacterial Cytochrome c Peroxidase Family
细菌细胞色素 c 过氧化物酶家族的结构、功能和多样性
基本信息
- 批准号:9240248
- 负责人:
- 金额:$ 32.41万
- 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 SitesAddressAdoptedAerobicAmino Acid SequenceBacteriaBase SequenceBindingBiochemistryBioinformaticsBurkholderiaCampylobacter jejuniCell RespirationCharacteristicsChemistryCitrobacterComplexCore ProteinCouplingCytochrome c GroupCytochrome c PeroxidaseDetectionDevelopmentDrug Metabolic DetoxicationElectrochemistryElectron Spin Resonance SpectroscopyElectron TransportElectronsElementsEnzymatic BiochemistryEnzymesEscherichia coliEvaluationFamilyFamily memberFreezingGenerationsGenomeGoalsGram-Negative BacteriaHealthHemeHumanHydrogen PeroxideIronLinkLungMapsModelingMolecularMolecular ConformationMossbauer SpectroscopyMutateN-terminalNamesNatureOperonOpticsOrganismOrthologous GeneOxidation-ReductionOxidesPaintPathogenicityPeroxidasesPeroxidesPhysiologicalPortraitsPost-Translational Protein ProcessingProcessPropertyProtein PrecursorsProteinsPseudomonas aeruginosaQuinonesReactionRegulationSalmonellaSideSiteSpectrum AnalysisStructureStructure-Activity RelationshipTyrosineUnited States National Institutes of HealthUrsidae FamilyVariantVertebral columnVibrioWaterX-Ray CrystallographyYersinia pestisantimicrobialbasecofactorcytochrome cdrug discoverydrug synthesisenteric pathogengene productheme ain vivoinsightmembermethylamine dehydrogenasemicrobialmicroorganismnoveloxidationparalogous genepathogenperiplasmprotein foldingtrait
项目摘要
PROJECT SUMMARY
Hydrogen peroxide is hazardous, though common side-productive of aerobic respiration; and many gram
negative bacteria synthesize cytochrome c peroxidase (bCCP) enzymes to detoxify the peroxide by reducing it
to water. bCCPs are a large family of enzymes that are marked by (at least two) c-type heme cofactors that are
covalently attached into the protein backbone by the action of the cytochrome c maturation machinery. bCCPs
encompass “true” bCCP enzymes that engage primarily in the chemistry implied by their name, but also other
enzymes such as MauG, which is responsible for the oxidative coupling of two tyrosine side-chains in the
methylamine dehydrogenase precursor (pre-MADH) to make functional MADH, that bears a unique
tryptophanyl tryptophane quinone (TTQ) cofactor. The structural bases for the differences of fundamental
chemistry displayed by bCCP and MauG are poorly understood to date, but are certainly linked to the
differences in the redox chemistry of conserved heme cofactors. In true bCCP enzymes, peroxidatic heme
(FeL) is reponsible for peroxide binding and reduction; while electrons are transmitted to the active site via a
heme that is over 500 mV higher in potential (FeH). In MauG, the potentials of the two heme cofactors are quite
close, though how this trait is linked to reactivity is enigmatic. This proposal will elucidate the structure-function
relationships of the bCCP family, including the distinctive chemistry of MauG vs. bCCP, and the molecular
determinants for activation found within the bCCP family. Further, we have employed bioinformatics
approaches to reveal new branches of the bCCP family; these include enzymes like YhjA found in enteric
pathogens such as E. coli. YhjA and its paralogs possess a third, N-terminal heme binding domain, with an
unknown function. A second new class of enzymes displays sequence-based traits that make it appear to be a
MauG paralog, but they are found predominantly in the lung pathogen Burkholderia and not in a mau operon.
Here will determine the chemistry of these novel bCCP in order to better understand the range of chemistry of
the entire family. The objectives of this proposal are to reveal the stucture-function relationship amongst the
members of the bCCP family, and to develop new models for the novel chemistries of enzymes such as Yhja,
and the previously unreported Burkholderia bCCPs. To do so, a combination of enzymology, protein
electrochemistry, and various spectroscopies (EPR, Mössbauer) and x-ray crystallography will be used to paint
a portrait of the reactivities and conformational dynamics displayed by the diverse bCCP family members. As
bCCP is an enzyme that is on the front-line of the native defenses of NIH Select List pathogens incuding
Pseudomonas aeruginosa, Burkholderia complex speices, Vibrio cholarae, Campylobacter jejuni, Escherichia
coli, Citrobacter, and Yersinia pestis, these studies will provide fundamental insight into the long-term
development of new antimicrobial compounds that will target the novel features of bCCP structure.
项目摘要
过氧化氢是危险的,虽然常见的副产品的有氧呼吸;和许多克
阴性细菌合成细胞色素c过氧化物酶(bCCP),通过还原过氧化物来解毒过氧化物
对水bCCP是由(至少两种)C型血红素辅因子标记的酶的大家族,
通过细胞色素c成熟机制的作用共价连接到蛋白质骨架中。bCCP
术语“bCCP酶”包括“真正的”bCCP酶,其主要参与由其名称所暗示的化学,但也包括其他化学。
酶,如MauG,其负责细胞中两个酪氨酸侧链的氧化偶联。
甲胺脱氢酶前体(pre-MADH),以产生功能性MADH,其具有独特的
胆甾烷基胆甾烷醌(TTQ)辅因子。基本面差异的结构基础
迄今为止,对bCCP和MauG所显示的化学性质知之甚少,但肯定与
保守的血红素辅因子的氧化还原化学的差异。在真正的bCCP酶中,过氧化物血红素
(FeL)负责过氧化物的结合和还原;而电子通过
血红素的电位高于500 mV(FeH)。在MauG中,两个血红素辅因子的潜力相当大,
接近,尽管这种特征与反应性的联系是神秘的。这一建议将阐明结构-功能
bCCP家族的关系,包括MauG与bCCP的独特化学性质,以及
bCCP家族中发现的激活决定因素。此外,我们还利用生物信息学
揭示bCCP家族新分支的方法;这些包括在肠道中发现的YhjA等酶
病原体如E.杆菌YhjA及其旁系同源物具有第三个N-末端血红素结合结构域,
未知函数第二类新的酶显示出基于序列的特征,使其看起来像是一种酶。
Mau操纵子,但它们主要存在于肺病原体伯克霍尔德氏菌中,而不是在Mau操纵子中。
这里将确定这些新型bCCP的化学性质,以便更好地理解这些化合物的化学性质范围。
整个家庭该建议的目的是揭示结构与功能之间的关系,
bCCP家族的成员,并开发新的模型,如Yhja,
以及之前未报道的伯克霍尔德菌bCCP。为了做到这一点,酶,蛋白质
电化学,各种光谱学(EPR,穆斯堡尔)和X射线晶体学将用于绘画
不同bCCP家族成员所显示的反应性和构象动力学的描述。作为
bCCP是一种酶,在NIH选择列表病原体的天然防御的前线,包括
铜绿假单胞菌、伯克霍尔德氏菌复合种、霍乱弧菌、空肠弯曲菌、埃希氏菌
大肠杆菌、柠檬酸杆菌和鼠疫耶尔森氏菌,这些研究将为长期的
开发针对bCCP结构新特征的新型抗菌化合物。
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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SEAN J ELLIOTT其他文献
SEAN J ELLIOTT的其他文献
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{{ truncateString('SEAN J ELLIOTT', 18)}}的其他基金
Redox Cofactor Diversity in Enzymatic Superfamilies
酶超家族中氧化还原辅因子的多样性
- 批准号:
10798645 - 财政年份:2020
- 资助金额:
$ 32.41万 - 项目类别:
Redox Cofactor Diversity in Enzymatic Superfamilies
酶超家族中氧化还原辅因子的多样性
- 批准号:
10623284 - 财政年份:2020
- 资助金额:
$ 32.41万 - 项目类别:
Redox Cofactor Diversity in Enzymatic Superfamilies
酶超家族中氧化还原辅因子的多样性
- 批准号:
10411899 - 财政年份:2020
- 资助金额:
$ 32.41万 - 项目类别:
Redox Reactions of the AdoMet Radical Enzyme Superfamily
AdoMet 自由基酶超家族的氧化还原反应
- 批准号:
9329461 - 财政年份:2016
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7937401 - 财政年份:2009
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7924120 - 财政年份:2006
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7144879 - 财政年份:2006
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7681465 - 财政年份:2006
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7492994 - 财政年份:2006
- 资助金额:
$ 32.41万 - 项目类别:
The Electrochemistry of Diheme Cytochrome c Peroxidases
二血红素细胞色素 c 过氧化物酶的电化学
- 批准号:
7279857 - 财政年份:2006
- 资助金额:
$ 32.41万 - 项目类别:
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