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.
项目总结
过氧化氢是危险的,尽管它是有氧呼吸的常见副产品;
阴性菌合成细胞色素c过氧化物酶(Bccp),通过还原过氧化氢来解毒。
到水里。BCCP是一个酶的大家族,以(至少两个)c型血红素辅因子为标志,这些辅因子是
在细胞色素c成熟机制的作用下共价连接到蛋白质骨架上。BCCP
包括“真正的”bCCP酶,主要参与其名称所暗示的化学作用,但也包括其他
酶,如MAUG,它负责氧化偶联两个酪氨酸侧链在
甲胺脱氢酶前体(Pre-MADH)制造功能性MADH,具有独特的
色氨酰色氨酸二酚(TTQ)辅因子。基本面差异的结构基础
到目前为止,bCCP和Maug所显示的化学物质知之甚少,但肯定与
保守的血红素辅因子在氧化还原化学上的差异。在真正的bCCP酶中,过氧化的血红素
(FEL)负责过氧化氢的结合和还原;而电子通过一种
电势高于500 mV的血红素(FeH)。在毛格,这两种血红素辅因子的潜力相当大。
很接近,尽管这一特征是如何与反应性联系在一起的还是个谜。这一建议将阐明其结构和功能
BCCP家族的关系,包括MAUG和bCCP的独特化学特征,以及分子
在bCCP家族中发现了激活的决定因素。此外,我们还利用了生物信息学
揭示bCCP家族新分支的方法;其中包括肠道中发现的YhjA等酶
病原体,如大肠杆菌。YhjA及其类似物具有第三个N-末端的血红素结合域,具有
未知函数。第二类新的酶显示了基于序列的特征,使其看起来像是一种
Maug Paralog,但它们主要在肺部病原体Burkholderia中发现,而不是在Mau操纵子中发现。
这里将测定这些新型bccp的化学成分,以便更好地了解其化学范围。
整个家族。这项建议的目的是揭示结构与功能之间的关系
BCCP家族的成员,并为酶的新化学成分开发新模型,如Yhja,
以及之前未报道的伯克霍尔德氏菌bccps。为了做到这一点,结合了酶学、蛋白质
电化学,以及各种光谱(EPR、穆斯堡尔)和X射线结晶学将被用于油漆
不同的bCCP家族成员的反应性和构象动力学的肖像。AS
BCCP是一种位于NIH精选病原体天然防御第一线的酶,包括
铜绿假单胞菌、复合伯克霍尔德氏菌、霍乱弧菌、空肠弯曲菌、大肠杆菌
大肠杆菌、柠檬酸杆菌和鼠疫耶尔森氏菌,这些研究将提供对长期
针对bccp结构的新特征开发新的抗菌化合物。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SEAN J ELLIOTT其他文献
SEAN J ELLIOTT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 32.41万 - 项目类别:
Research Grant