Expanding the Catalytic Repertoire of Heme-based Dioxygenases
扩展血红素双加氧酶的催化能力
基本信息
- 批准号:10719622
- 负责人:
- 金额:$ 38.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingActive SitesApoproteinsBindingBiological AssayChemicalsChemistryCollaborationsCommunicationComprehensionConsumptionCoupledCytochrome P450DataDioxygenasesDiseaseDistalDrug TargetingElectron TransportElectronsElectrostaticsEnvironmentFlavin MononucleotideGoalsGuidelinesHealthHemeHemeproteinsHistidineHumanHuman ActivitiesHydrogen PeroxideKineticsKnowledgeKynurenineLearningMalignant NeoplasmsMass Spectrum AnalysisMediatorMutagenesisOxidasesOxygenOxygenasesPeroxidasesPhysiologicalProcessPropertyProteinsProtonsPublic HealthRaman Spectrum AnalysisReactionResearchSerineSolventsSpectrum AnalysisStructureSuperoxidesTechniquesTestingTherapeuticTimeTryptophanTryptophan 2,3 DioxygenaseWaterWorkX-Ray Crystallographyabsorptiondisorder controldisorder preventionexperimental studyheme ahuman diseaseinsightmolecular dynamicsnovelpressureprogramssimulationstructural determinants
项目摘要
PROJECT SUMMARY
Human tryptophan dioxygenase (hTDO) and indoleamine 2, 3-dioxygenase 1 (hIDO1) are two hemeproteins
that catalyze the dioxygenation reaction of L-tryptophan (Trp) to N-formyl kynurenine. Although it is
generally believed that electrons and protons are crucial for oxygen activation by hemeproteins, the
dioxygenases are so unique that they catalyze the oxidative ring cleavage reaction of Trp without consuming
any electrons or protons. With time-resolved resonance Raman spectroscopy, combined with QM/MM
simulations, we have established a substrate-assisted mechanism accounting for the unusual chemistry
catalyzed by the dioxygenases. Recently, we discovered that, in addition to the Trp dioxygenation activity,
hTDO can bind NAD(P)H in the active site, thereby repurposing it for (i) a heme oxygenase (HO) reaction,
which converts the active holoprotein to the inactive apoprotein, (ii) an oxidase reaction, which reduces O2 to
superoxide, and (iii) a peroxidase reaction, which reduces H2O2 to water. Although hTDO and hIDO1 share
a common active site structure and catalyze the Trp dioxygenation reaction with the same mechanism, hIDO1
does not exhibit the HO activity, but it retains the oxidase and peroxidase activities. These exciting new
findings expand the substrate portfolio and the catalytic repertoire of the heme-based dioxygenases. The major
goal of this project is to decipher the structural determinants dictating the novel enzymatic activities of the two
dioxygenases. The scientific premise of this project is that the comprehension of the new enzymatic activities
of hTDO and hIDO1 will further our knowledge in heme oxygen chemistry and provide new insights into their
physiological functions, thereby offering guidelines for disease control and prevention.
项目摘要
人色氨酸双加氧酶(hTDO)和吲哚胺2,3-双加氧酶1(hIDO 1)是两种血红素蛋白
其催化L-色氨酸(Trp)至N-甲酰基犬尿氨酸的二氧化反应。虽然
一般认为电子和质子对于血红素蛋白的氧活化是至关重要的,
双加氧酶是如此独特,以至于它们催化Trp的氧化环裂解反应,而不消耗
任何电子或质子。利用时间分辨共振拉曼光谱,结合QM/MM
模拟,我们已经建立了一个基板辅助机制占不寻常的化学
由双加氧酶催化最近,我们发现,除了色氨酸双氧化活性,
hTDO可以在活性位点结合NAD(P)H,从而将其重新用于(i)血红素加氧酶(HO)反应,
其将活性全蛋白转化为非活性脱辅基蛋白,(ii)氧化酶反应,其将O2还原为
过氧化物,和(iii)过氧化物酶反应,其将H2 O2还原成水。虽然hTDO和hIDO 1共享
一个共同的活性中心结构,并以相同的机理催化色氨酸双加氧反应,hIDO 1
不显示HO活性,但保留了氧化酶和过氧化物酶活性。这些令人兴奋的新
研究结果扩大了底物组合和血红素为基础的双加氧酶的催化库。主要
该项目的目标是破译决定这两种酶的新酶活性的结构决定因素。
双加氧酶本课题的科学前提是对新酶活性的理解
hTDO和hIDO 1的研究将进一步加深我们在血红素氧化学方面的知识,并为它们的生物学特性提供新的见解。
生理功能,从而为疾病控制和预防提供指导。
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 }}
Syun-Ru Yeh其他文献
Syun-Ru Yeh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('Syun-Ru Yeh', 18)}}的其他基金
Structure and Function of Heme-based Dioxygenases
血红素双加氧酶的结构和功能
- 批准号:
10398107 - 财政年份:2016
- 资助金额:
$ 38.64万 - 项目类别:
Structure and Function of Heme-based Dioxygenases
血红素双加氧酶的结构和功能
- 批准号:
10614501 - 财政年份:2016
- 资助金额:
$ 38.64万 - 项目类别:
Structure and Function of Heme-based Dioxygenases
血红素双加氧酶的结构和功能
- 批准号:
9973608 - 财政年份:2016
- 资助金额:
$ 38.64万 - 项目类别:
Catalytic and regulatory mechanisms of human Tryptophan Dioxygenase
人色氨酸双加氧酶的催化和调节机制
- 批准号:
9107183 - 财政年份:2016
- 资助金额:
$ 38.64万 - 项目类别:
Catalytic and Inhibitory Mechanisms in Indoleamine 2,3-dioxygenase
吲哚胺 2,3-双加氧酶的催化和抑制机制
- 批准号:
8257584 - 财政年份:2010
- 资助金额:
$ 38.64万 - 项目类别:
Catalytic and Inhibitory Mechanisms in Indoleamine 2,3-dioxygenase
吲哚胺 2,3-双加氧酶的催化和抑制机制
- 批准号:
7889844 - 财政年份:2010
- 资助金额:
$ 38.64万 - 项目类别:
Catalytic and Inhibitory Mechanisms in Indoleamine 2,3-dioxygenase
吲哚胺 2,3-双加氧酶的催化和抑制机制
- 批准号:
8078881 - 财政年份:2010
- 资助金额:
$ 38.64万 - 项目类别:
Catalytic and Inhibitory Mechanisms in Indoleamine 2,3-dioxygenase
吲哚胺 2,3-双加氧酶的催化和抑制机制
- 批准号:
8451545 - 财政年份:2010
- 资助金额:
$ 38.64万 - 项目类别:
相似海外基金
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334970 - 财政年份:2024
- 资助金额:
$ 38.64万 - 项目类别:
Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
- 批准号:
2400195 - 财政年份:2024
- 资助金额:
$ 38.64万 - 项目类别:
Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334969 - 财政年份:2024
- 资助金额:
$ 38.64万 - 项目类别:
Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
- 批准号:
23K04919 - 财政年份:2023
- 资助金额:
$ 38.64万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
- 批准号:
22KJ2957 - 财政年份:2023
- 资助金额:
$ 38.64万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
- 批准号:
23K04494 - 财政年份:2023
- 资助金额:
$ 38.64万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
- 批准号:
23K13831 - 财政年份:2023
- 资助金额:
$ 38.64万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
- 批准号:
2238379 - 财政年份:2023
- 资助金额:
$ 38.64万 - 项目类别:
Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
- 批准号:
2154399 - 财政年份:2022
- 资助金额:
$ 38.64万 - 项目类别:
Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
- 批准号:
RGPIN-2019-06633 - 财政年份:2022
- 资助金额:
$ 38.64万 - 项目类别:
Discovery Grants Program - Individual