Heme and Nonheme Transition Metal Complexes, Reactivity, and Mechanism
血红素和非血红素过渡金属配合物、反应性和机制
基本信息
- 批准号:10623095
- 负责人:
- 金额:$ 18.05万
- 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:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAddressAnabolismArthritisBiological ProcessBiomimeticsChemistryComplexCysteine dioxygenaseCytochrome P450DiagnosticDioxygenDioxygenasesDiseaseDrug Metabolic DetoxicationElectronicsEncephalopathiesEnergy TransferEnzymesEventGenetic DiseasesHealthHemeHumanHydrogen BondingHydroxylationIndolesIronKineticsKnowledgeLigandsMalignant NeoplasmsMediatingMetabolismMetalsMethodologyMixed Function OxygenasesModificationMolecular WeightNeurodegenerative DisordersOxygenPathway interactionsPlayProcessPropertyProteinsRoleStructure-Activity RelationshipSulfhydryl CompoundsSulfoxideSulfurSystemTherapeuticThermodynamicsTransition ElementsTryptophanadductanalogelectronic structureenzyme mechanismindoleamineisopenicillin Nmetal complexmetalloenzymeoxidationpersulfidessmall molecule
项目摘要
Project Summary
This proposal focuses on the activation and utilization of dioxygen by heme and nonheme transition metal centers
in metalloenzymes and in related synthetic systems. A subset of nonheme iron enzymes utilize a single iron
center to activate dioxygen and mediate the oxidation of various substrates, including sulfur substrates as seen
in thiol dioxygenases (TDOs) (e.g. cysteine dioxygenase (CDO)), persulfide dioxygenases (PDOs) (e.g.
ethylmalonic encephalopathy protein (ETHE1)), sulfoxide synthases (e.g. EgtB, OvoA), and isopenicillin N
synthase (IPNS). The related nonheme iron hydroxylases (e.g. TauD) and halogenases (e.g. SyrB2) also
activate O2 with a single iron center to transform C-H bonds into C-X (X = OH, Cl) groups. Many questions remain
regarding the mechanisms of action of these proteins, although the proposed pathways for these different
enzymes include several common iron/oxygen intermediates. Heme enzymes also activate O2 for similar
oxidative chemistry, such as C-H hydroxylation carried out by the monooxygenase cytochrome P450 (CYP), or
the C-C bond cleavage and dioxygenation of indoles carried out by tryptophan and indoleamine dioxygenase
(TDO/IDO). The proposed efforts involve the synthesis of biomimetic heme and nonheme iron complexes that
will be used to examine how the first and second coordination spheres influence O2 activation and substrate
oxidations. Efforts will be made to characterize metastable transition metal/O2 species (e.g. M-O2, M-OOH, M=O,
M-OH) that are proposed as key intermediates in heme and nonheme O2 activation. Characterization of these
species in structurally well-defined complexes will provide support for the analogous, putative intermediates in
the enzymatic systems. The feasibility of key bond-making and bond-breaking events will be established by
examining the reactivity of these metal/oxygen adducts with various substrates. Mechanistic questions will be
addressed through comprehensive thermodynamic and kinetic studies. Systematic modifications will be made
to these low molecular weight complexes through established synthetic methodologies, providing atomic-level
control over their geometric/electronic structures. This approach provides a means to establish structure-function
relationships that can be challenging or impossible to obtain when studying the enzymes alone. Questions to be
addressed include what are the key intermediates during heme and nonheme iron activation of O2? What are
the key spectroscopic features of these intermediates? Which of these species are capable of oxidizing which
substrates? How does the structural and electronic properties of the ligands holding the metal center influence
the O2 activation process? What controls the selectivity of substrate oxidations? Addressing these questions
should lead to new knowledge regarding how heme and nonheme iron enzymes activate O2 and selectively
oxidize substrates. These enzymes participate in biological processes that are essential for human health and
disease, making them targets for both diagnostic and therapeutic treatments.
项目摘要
该建议的重点是血红素和非血红素过渡金属中心的活化和利用双氧
在金属酶和相关的合成系统中。非血红素铁酶的一个子集利用单一的铁
中心,以活化分子氧并介导各种底物的氧化,包括所见的硫底物
在硫醇双加氧酶(TDO)(例如半胱氨酸双加氧酶(CDO))、过硫化物双加氧酶(PDO)(例如,
乙基丙二酸脑病蛋白(ETHE 1))、亚砜脱氢酶(例如EgtB、OvoA)和异青霉素N
合成酶(IPNS)。相关的非血红素铁羟化酶(例如TauD)和卤化酶(例如SyrB 2)也
用单个铁中心活化O2以将C-H键转化为C-X(X = OH,Cl)基团。还有许多问题
关于这些蛋白质的作用机制,虽然这些不同的蛋白质的拟议途径,
酶包括几种常见的铁/氧中间体。血红素酶也能激活O2,
氧化化学,例如由单加氧酶细胞色素P450(CYP 14)进行的C-H羟基化,或
色氨酸和吲哚胺双加氧酶进行吲哚的C-C键断裂和双加氧
(TDO/IDO)。所提出的努力涉及仿生血红素和非血红素铁络合物的合成,
将被用来研究如何第一和第二配位球影响O2活化和基板
氧化将努力表征亚稳过渡金属/O2物质(例如,M-O2、M-OOH、M=O,
M-OH)被认为是血红素和非血红素O2活化的关键中间体。表征这些
在结构上明确定义的复合物中的物种将为类似的,推定的中间体提供支持,
酶系统。关键的债券制定和债券违约事件的可行性将通过
检查这些金属/氧加合物与各种底物的反应性。机械问题将是
通过全面的热力学和动力学研究解决。将进行系统的修改
这些低分子量的复合物通过建立合成方法,提供原子水平的
控制其几何/电子结构。这种方法提供了一种建立结构-功能的方法
这些关系在单独研究酶时可能具有挑战性或不可能获得。疑问待
包括血红素和非血红素铁激活O2过程中的关键中间体是什么?是什么
这些中间体的关键光谱特征这些物质中的哪一种能够氧化
基质?金属中心配体的结构和电子性质如何影响
O2活化过程是什么控制着底物氧化的选择性?解决这些问题
应该导致关于血红素和非血红素铁酶如何激活O2和选择性地
氧化底物。这些酶参与对人类健康至关重要的生物过程,
疾病,使它们成为诊断和治疗的目标。
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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David P Goldberg其他文献
David P Goldberg的其他文献
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{{ truncateString('David P Goldberg', 18)}}的其他基金
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
10809294 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
9929886 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
10218201 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
10389327 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
10426248 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
9203896 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Synthetic Nonheme Iron O2 Activation and S-Oxygenation
合成非血红素铁 O2 活化和 S 氧化
- 批准号:
10671670 - 财政年份:2016
- 资助金额:
$ 18.05万 - 项目类别:
Reactivity of Manganese and Iron Metalloenzyme Models
锰和铁金属酶模型的反应性
- 批准号:
9068158 - 财政年份:2013
- 资助金额:
$ 18.05万 - 项目类别:
Reactivity of Manganese and Iron Metalloenzyme Models
锰和铁金属酶模型的反应性
- 批准号:
10442664 - 财政年份:2013
- 资助金额:
$ 18.05万 - 项目类别:
Reactivity of Manganese and Iron Metalloenzyme Models
锰和铁金属酶模型的反应性
- 批准号:
8852634 - 财政年份:2013
- 资助金额:
$ 18.05万 - 项目类别:
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