Heme and Nonheme Transition Metal Complexes, Reactivity, and Mechanism

项目摘要 这项建议侧重于血红素和非血红素过渡金属中心对氧气的活化和利用。 在金属酶和相关的合成系统中。非血红素铁酶的子集利用单一的铁 中心激活氧气并调节各种底物的氧化，包括硫底物，如图所示 在硫醇双加氧酶(TDO)(如半胱氨酸双加氧酶(CDO))中，过硫化物双加氧酶(PDO)(如：硫代双加氧酶)、硫醇双加氧酶(TDO)、过硫代双加氧酶(TDO)、过硫代双加氧酶(TDO)、硫醇双加氧酶(TDO)、过硫化物双加氧酶(PDO)、半胱氨酸双加氧酶(CDO)等。 乙基丙二酸脑病蛋白(ETHE1)、亚砜合成酶(如EgtB、OvoA)和异青霉素N 合酶(IPNS)。相关的非血红素铁羟基酶(例如TauD)和卤代酶(例如SyrB2)还 用一个铁中心活化O2，将C-H键转化为C-X(X=OH，Cl)基团。许多问题仍然存在 关于这些蛋白质的作用机制，尽管对这些蛋白质提出的途径不同 酶包括几种常见的铁/氧中间体。血红素酶也能激活氧 氧化化学，例如由单加氧酶细胞色素P450(CYP)进行的C-H羟基化；或 色氨酸和吲哚胺双加氧酶对吲哚的C-C键断裂和加氧作用 (TDO/IDO)。拟议的努力涉及合成仿生血红素和非血红素铁络合物， 将被用来研究第一和第二配位球如何影响O2的激活和底物 氧化作用。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)，被认为是血红素和非血红素O2活化的关键中间体。对这些的描述 结构明确的络合物中的物种将为类似的、假定的中间体提供支持 酶系统。将通过以下方式确定关键做债和违约事件的可行性 检测这些金属/氧加合物与不同底物的反应活性。机械性的问题将是 通过全面的热力学和动力学研究加以解决。将进行系统的修改 通过已建立的合成方法，提供原子级的 对其几何/电子结构的控制。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，这些关系可能是具有挑战性的，或者是不可能获得的。有待解决的问题 讨论包括在血红素和非血红素铁激活O2的过程中有哪些关键的中间产物？何谓 这些中间体的主要光谱特征是什么？这些物种中的哪些能够氧化哪些 底物？金属中心配位体的结构和电子性质如何影响 氧气的激活过程？是什么控制着底物氧化的选择性？回答这些问题 应该带来关于血红素和非血红素铁酶如何激活O2和选择性地激活O2和 氧化底物。这些酶参与对人类健康至关重要的生物过程，并 疾病，使它们成为诊断和治疗的目标。

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.