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
• 负责人: David P Goldberg
• 金额: $ 1.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10809294
• 关键词: Alzheimer' s Disease; Arthritis; Binding; Binding Sites; Biology; Carbon; Complement; Complex; Cysteine dioxygenase; Dioxygen; Dioxygenases; Disease; Electron Spin Resonance Spectroscopy; Encephalopathies; Enzymes; Future; Genetic Diseases; Health; Human; Hydroxides; Iron; Iron Compounds; Knowledge; Malignant Neoplasms; Mediating; Methods; Modeling; Mononuclear; Neurodegenerative Disorders; Oxygen; Oxygenases; Parkinson Disease; Pathway interactions; Penicillins; Process; Property; Proteins; Reaction; Roentgen Rays; Spectrum Analysis; Structure; Sulfhydryl Compounds; Sulfoxide; Sulfur; System; Transition Elements; absorption; analog; catalyst; cold temperature; computer studies; design; enzyme mechanism; insight; isopenicillin N; oxidation; persulfides

Project Summary This proposal focuses on the fundamental structural, functional, and mechanistic requirements for the activation of O2 by nonheme iron complexes and related enzymes. Dioxygen is processed by nonheme iron centers in biology as part of a range of critical functions, including the mono- and di-oxygenation of organic substrates, as well as the formation of C-S and C-halide bonds. The oxygenation of organic substrates is mediated by nonheme iron oxygenases, and an important subclass of these enzymes oxygenate sulfur sites bound to the iron center. This subclass includes the thiol dioxygenases (TDOs), such as mammalian cysteine dioxygenase (CDO), and the persulfide dioxygenases (PDOs), such as mammalian ethylmalonic encephalopathy protein (ETHE1). The mechanisms of action of the TDOs and PDOs are poorly understood, although several common iron/oxygen intermediates have been proposed. The sulfoxide synthases EgtB and OvoA are related mononuclear, nonheme Fe enzymes that utilize O2 to carry out both S-oxygenation and C-S bond formation, as does isopenicillin N synthase (IPNS), which employs Fe and O2 in the biosynthetic pathway of penicillin. The C-S bond formation in IPNS occurs via selective carbon radical addition to a sulfur bound to Fe, a process similar to what occurs in nonheme Fe α-KG halogenases. A number of fundamental mechanistic questions remain unanswered regarding these enzymes. This proposal describes the synthesis and study of synthetic nonheme iron compounds designed to model certain aspects of structure and function related to the TDO/PDOs, sulfoxide synthases, IPNS, and the α-KG halogenases. Proposed efforts also include select studies on the enzyme CDO, which parallel and complement the model compounds. A focus of the proposal is to characterize reactive, Fe/O2-derived species that are analogs of key intermediates thought to be important in nonheme iron-mediated O2 activation. Characterization of these species in structurally well-defined synthetic complexes will provide precedent and support for the analogous, proposed intermediates in the enzymatic systems. The feasibility of proposed, key bond-making/bond-breaking steps will be established. Methods designed to trap and/or characterize Fe/O2 species will be used, including low temperatures and a suite of advanced spectroscopies (low-temperature UV- vis, electron paramagnetic resonance, resonance Raman, Mössbauer, X-ray absorption). Computational studies will be employed to help interpret and predict structural and spectroscopic properties as well as reaction pathways. The selective reactivity of carbon radicals with iron-heteroatom bonds will also be assessed, taking advantage of a unique set of new, structurally characterized ferric hydroxide complexes. These studies should lead to significant advances in our fundamental knowledge regarding how nonheme Fe enzymes activate O2 and selectively oxidize substrates. This knowledge should also provide guidance for the design of future transition metal catalysts. The misfunctioning of these enzymes have been implicated in a variety of diseases, including neurodegenerative disorders (Alzheimer's, Parkinson's), arthritis, cancer, and genetic disorders.

项目摘要 该提案侧重于激活的基本结构、功能和机械要求 非血红素铁复合物和相关酶的O2。分子氧由非血红素铁中心加工， 生物学作为一系列关键功能的一部分，包括有机基质的单氧化和双氧化， 以及C-S和C-卤键的形成。有机底物的氧化是由非血红素介导的 铁加氧酶和这些酶的一个重要亚类是与铁中心结合的硫位点。 该亚类包括硫醇双加氧酶（TDO），如哺乳动物半胱氨酸双加氧酶（CDO），和 过硫化物双加氧酶（PDO），如哺乳动物乙基丙二酸脑病蛋白（ETHE 1）。的 TDO和PDO的作用机制知之甚少，尽管几种常见的铁/氧 已经提出了中间体。亚砜脱氢酶EgtB和OvoA与单核、非血红素 Fe酶利用O2进行S-氧化和C-S键形成，如异青霉素N 合成酶（IPNS），其在青霉素的生物合成途径中利用Fe和O2。C-S键的形成 IPNS通过选择性碳自由基加成到与Fe结合的硫上而发生，该过程类似于 非血红素Fe α-KG卤化酶。一些基本的机械问题仍然没有答案， 这些酶。本文介绍了合成非血红素铁化合物的合成和研究 设计用于模拟与TDO/PDO，亚砜脱氢酶，IPNS， 和α-KG卤化酶。拟议的努力还包括对CDO酶的选择研究，该研究与 补充模型化合物。该提案的一个重点是表征反应性的Fe/O2衍生物种 它们是被认为在非血红素铁介导的O2活化中重要的关键中间体的类似物。 在结构明确的合成复合物中表征这些物质将提供先例， 支持类似的，建议在酶系统的中间体。建议的可行性，关键 将建立键合/键断步骤。设计用于捕获和/或表征Fe/O2的方法 物种将被使用，包括低温和一套先进的光谱（低温紫外- 维斯，电子顺磁共振，共振拉曼，穆斯堡尔，X射线吸收）。计算研究 将被用来帮助解释和预测结构和光谱特性以及反应 途径。还将评估碳自由基与铁-杂原子键的选择性反应性， 这是一组独特的新的，结构特征的氢氧化铁复合物的优点。这些研究应 导致我们关于非血红素铁酶如何激活O2的基础知识的重大进展 并选择性地氧化底物。这些知识也应该为未来的设计提供指导。 过渡金属催化剂这些酶的功能失调与多种疾病有关， 包括神经退行性疾病（阿尔茨海默氏症、帕金森氏症）、关节炎、癌症和遗传性疾病。

项目成果

Activation of Dioxygen by Iron and Manganese Complexes: A Heme and Nonheme Perspective.

• DOI: 10.1021/jacs.6b05251
• 发表时间: 2016-09-14
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Sahu S;Goldberg DP
• 通讯作者: Goldberg DP

Structures, Spectroscopic Properties, and Dioxygen Reactivity of 5- and 6-Coordinate Nonheme Iron(II) Complexes: A Combined Enzyme/Model Study of Thiol Dioxygenases.

• DOI: 10.1021/jacs.8b08349
• 发表时间: 2018-11-07
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Gordon JB;McGale JP;Prendergast JR;Shirani-Sarmazeh Z;Siegler MA;Jameson GNL;Goldberg DP
• 通讯作者: Goldberg DP

Observation of Radical Rebound in a Mononuclear Nonheme Iron Model Complex.

• DOI: 10.1021/jacs.7b12707
• 发表时间: 2018-03-28
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Pangia TM;Davies CG;Prendergast JR;Gordon JB;Siegler MA;Jameson GNL;Goldberg DP
• 通讯作者: Goldberg DP

Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe-S Cluster Biosynthesis.

• DOI: 10.1021/jacs.2c06338
• 发表时间: 2022-09-28
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Srour, Batoul;Gervason, Sylvain;Hoock, Maren Hellen;Monfort, Beata;Want, Kristian;Larkem, Djabir;Trabelsi, Nadine;Landrot, Gautier;Zitolo, Andrea;Fonda, Emiliano;Etienne, Emilien;Gerbaud, Guillaume;Mueller, Christina Sophia;Oltmanns, Jonathan;Gordon, Jesse B.;Yadav, Vishal;Kleczewska, Malgorzata;Jelen, Marcin;Toledano, Michel B.;Dutkiewicz, Rafal;Goldberg, David P.;Schuenemann, Volker;Guigliarelli, Bruno;Burlat, Benedicte;Sizun, Christina;D'Autreaux, Benoit
• 通讯作者: D'Autreaux, Benoit

Nonheme Iron(III) Azide and Iron(III) Isothiocyanate Complexes: Radical Rebound Reactivity, Selectivity, and Catalysis.

• DOI: 10.1021/jacs.2c07224
• 发表时间: 2022-11-16
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Yadav, Vishal;Wen, Lyupeng;Rodriguez, Rodolfo J.;Siegler, Maxime A.;Goldberg, David P.
• 通讯作者: Goldberg, David P.