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Reactivity of Manganese and Iron Metalloenzyme Models

锰和铁金属酶模型的反应性

基本信息

批准号：
10624814
负责人：
David P Goldberg
金额：
$ 29.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10624814
关键词：
Active Sites Address Anabolism Binding Biological Process Biomimetics Carbon Catalysis Cell Nucleus Charge Chloride Peroxidase Complement Complex Contracts Coupled Cytochrome P450 Diagnostic Dioxygen Dioxygenases Disease Dissociation Drug Metabolic Detoxication Electron Transport Electronics Energy Transfer Enzymes Event Exhibits Family Free Energy Funding Goals Halogens Health Heme Hemeproteins Human Hydrocarbons Hydrogen Bonding Hydrogen Peroxide Hydroxyl Radical Indoles Iron Kinetics Learning Ligands Ligation Manganese Measures Mediating Metabolism Metals Methodology Methods Modeling Modification Nature Outcome Oxidants Oxidation-Reduction Oxygen Pathway interactions Pattern Play Porphyrins Process Property Proteins Protons Reaction Research Role Series Structure Structure-Activity Relationship System Techniques Therapeutic Thermodynamics Time Tryptophan Tryptophan 2,3 Dioxygenase Tryptophanase Work adduct analog catalyst cofactor cold temperature computer studies corrole design electronic structure enzyme mechanism feasibility testing knowledge base metalloenzyme novel oxidation programs small molecule stop flow technique

项目摘要

Project Summary Heme proteins participate in many essential biological processes that are important to human health and disease, and they are targets of both diagnostic and therapeutic treatments. An important subset of these proteins are enzymes that activate dioxygen (O2) or its reduced analogs (e.g. H2O2). These enzymes utilize the same iron cofactor to mediate a wide range of reactions, including mono- and dioxygenation of organic substrates, C-H activation, desaturation, and C-C bond cleavage. How nature tunes the metal center and active site of these enzymes to mediate such a wide range of functionality is a question of fundamental significance that continues to motivate significant research. This proposal focuses on the synthesis and reactivity of small- molecule model complexes of key intermediates, and their related bond-making/bond-breaking events, proposed in the mechanisms of the thiolate-ligated heme enzymes Cytochrome P450 (CYP), chloroperoxidase (CPO), and aromatic peroxygenase (APO), and the non-thiolate-ligated heme dioxygenases tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO). The thiolate-ligated heme enzymes are capable of oxidizing hydrocarbon C-H bonds, and the proposed mechanism involves H-atom transfer (HAT) (proton-coupled electron- transfer, PCET) from R-H to an intermediate called Compound-I (Fe=O), followed by hydroxyl transfer (“rebound”) from protonated Compound-II (Fe-OH) to give the ROH product. However, the rebound step can be diverted to other pathways, leading to distinctly different reaction outcomes. Many questions remain regarding the fundamental structural, electronic, thermodynamic and kinetic factors that control both HAT and rebound steps. In contrast, TDO/IDO are proposed to rely on an Fe(O2) adduct and Compound-II as active oxidants, although much remains to be learned about this mechanism. Efforts in this proposal will address these questions through the synthesis and study of biomimetic M=O, M-OH, and M-O2 species that will be prepared with tailored porphyrinoid ligands designed to stabilize these species and allow for their direct study. These ligands include ring-contracted corroles (Crl) and corrolazines (Cz), which have a modified porphyrin nucleus which presents a trianionic (3-) charge to the metal, similar to a thiolate-ligated heme active site. Our previous efforts showed that the Crl and Cz platforms provide access to novel species not seen with conventional porphyrins, including a Cpd-I analog with the same spin ground state as found in CYP and CPO, and the first example of a protonated Cpd-II model. Systematic modifications can be made to these small-molecule models through established synthetic methodologies, providing atomic-level control over their geometric/electronic structures, and providing a means to establish structure-function relationships that can be challenging or impossible to obtain when studying the enzymes alone. The long-term goals of the proposed work are: 1) to address fundamental questions related to heme enzyme reactivity and mechanism, and 2) to build the knowledge base regarding synthetic porphyrinoid complexes for applications in small-molecule activation and catalysis.

项目总结

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dramatic influence of an anionic donor on the oxygen-atom transfer reactivity of a Mn(V) -oxo complex.

DOI：
10.1002/chem.201404349
发表时间：
2014-11-03
期刊：
CHEMISTRY-A EUROPEAN JOURNAL
影响因子：
4.3
作者：
Neu, Heather M.;Quesne, Matthew G.;Yang, Tzuhsiung;Prokop-Prigge, Katharine A.;Lancaster, Kyle M.;Donohoe, James;DeBeer, Serena;de Visser, Sam P.;Goldberg, David P.
通讯作者：
Goldberg, David P.

A Balancing Act: Stability versus Reactivity of Mn(O) Complexes.