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

• 批准号: 10623095
• 负责人: David P Goldberg
• 金额: $ 18.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10623095
• 关键词: Active Sites; Address; Anabolism; Arthritis; Biological Process; Biomimetics; Chemistry; Complex; Cysteine dioxygenase; Cytochrome P450; Diagnostic; Dioxygen; Dioxygenases; Disease; Drug Metabolic Detoxication; Electronics; Encephalopathies; Energy Transfer; Enzymes; Event; Genetic Diseases; Health; Heme; Human; Hydrogen Bonding; Hydroxylation; Indoles; Iron; Kinetics; Knowledge; Ligands; Malignant Neoplasms; Mediating; Metabolism; Metals; Methodology; Mixed Function Oxygenases; Modification; Molecular Weight; Neurodegenerative Disorders; Oxygen; Pathway interactions; Play; Process; Property; Proteins; Role; Structure-Activity Relationship; Sulfhydryl Compounds; Sulfoxide; Sulfur; System; Therapeutic; Thermodynamics; Transition Elements; Tryptophan; adduct; analog; electronic structure; enzyme mechanism; indoleamine; isopenicillin N; metal complex; metalloenzyme; oxidation; persulfides; small molecule

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.

项目概要 该提案重点关注血红素和非血红素过渡金属中心对双氧的激活和利用 在金属酶和相关合成系统中。非血红素铁酶的一个子集利用单一铁 中心激活双氧并介导各种底物的氧化，包括所见的硫底物 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 (ETHE1))、亚砜合酶（例如 EgtB、OvoA）和异青霉素 N 合酶（IPNS）。相关的非血红素铁羟化酶（例如 TauD）和卤化酶（例如 SyrB2）也 用单个铁中心激活 O2，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，尽管这些不同的拟议途径 酶包括几种常见的铁/氧中间体。血红素酶还可以激活 O2 以实现类似的作用 氧化化学，例如单加氧酶细胞色素 P450 (CYP) 进行的 C-H 羟基化，或 由色氨酸和吲哚胺双加氧酶进行的吲哚的C-C键断裂和双加氧 （TDO/IDO）。拟议的工作涉及仿生血红素和非血红素铁复合物的合成， 将用于检查第一和第二配位层如何影响 O2 活化和底物 氧化。将努力表征亚稳态过渡金属/O2 物种（例如 M-O2、M-OOH、M=O、 M-OH）被提议作为血红素和非血红素 O2 激活的关键中间体。这些的表征 结构明确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。关键的债券形成和债券断裂事件的可行性将由 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来解决。将进行系统性修改 通过已建立的合成方法对这些低分子量复合物进行合成，提供原子级 控制它们的几何/电子结构。这种方法提供了一种建立结构-功能的方法 当单独研究酶时，这些关系可能具有挑战性或不可能获得。待问问题 解决的问题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？什么是 这些中间体的关键光谱特征是什么？这些物种中哪些能够氧化哪些 基材？持有金属中心的配体的结构和电子性质如何影响 O2激活过程？什么控制底物氧化的选择性？解决这些问题 应该会带来关于血红素和非血红素铁酶如何激活 O2 并选择性地产生新知识 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。