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Nitrogen Oxides and Heme

氮氧化物和血红素

基本信息

批准号：
7413877
负责人：
George Bannerman Richter-Addo
金额：
$ 21.28万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413877
关键词：
Amines Anabolism Anions Area Binding Biochemical Biochemistry Bioinorganic Chemistry Biological Chemicals Chemistry Complex Condition Consumption Coupling Crystallography Distal Electrochemistry Electronics Environment Enzymes Event Fireflies Generations Genetic Recombination Grant Health Heme Heme Iron Hemeproteins Hemoglobin Hydroxylamine Hypoxia Inorganic Nitrogen Compounds Ions Iron Isomerism Ligands Light Mammals Metabolic Metals Modeling Mono-S Mutagenesis Myoglobin NBL1 gene Nature Nitric Oxide Nitric Oxide Donors Nitric Oxide Pathway Nitrite Reductase Nitrites Nitrogen Nitrogen Oxides Nitrosamines Oxygen Pathway interactions Physiological Play Porphyrins Production Proteins Public Health Range Reaction Research Role Sampling Signal Transduction Spectrum Analysis System Testing Vasodilation adduct base chemical property chlorin density fascinate hyponitrite in vivo infrared spectroscopy insight interest metalloenzyme mutant nitric oxide reductase nitroxyl oxidation research study small molecule

项目摘要

Iron plays significant roles in the chemistry of nitrogen oxides in the biosphere. The simplest nitrogen oxide, NO (nitric oxide), is a small paramagnetic molecule that binds to heme iron to result in various biological events ranging from vasodilation to the enabling of light flashes in fireflies. Heme iron is intricately involved in the mammalian biosynthesis of NO and in physiological signaling by NO. The diverse biological effects of NO when bound to heme raises intriguing questions regarding the identities and chemical properties of the FeNO moieties. The related nitrite anion is now recognized to play key roles in NO biochemistry, and may be the major storage form of NO in mammals. Interestingly, myoglobin (Mb) and hemoglobin have recently been proposed to act as nitrite reductases under hypoxic conditions, generating NO in the oxygen-deficient environment. In this proposed research, we will utilize a combination of synthesis, characterization, spectroscopy, small molecule and protein crystallography, mutagenesis, and theoretical calculations to probe fundamental issues concerning the nature of the interaction of NO, nitrite, and related nitrogen oxides with biologically relevant heme iron. We will prepare, in Specific Aim 1, a representative set of N-base and thiolate liganded heme model compounds with NO ligands and characterize them by spectroscopy (IR, EPR, rR, UV-vis), electrochemistry, and crystallography. We will utilize DFT calculations to provide further insight into the electronics of the FeNO moieties. MbNO and its mutants will be examined as well. In Specific Aim 2, we will characterize the reaction pathways (NO linkage isomerism, reactions with H-donors, NO coupling reactions, etc) available to the FeNO group in heme and heme model compounds. Nitrite adducts of heme models and Mb (and distal pocket mutants) will be prepared and characterized in Specific Aim 3, and they will be examined for their ability to convert nitrite to NO. Relevance to public health: Mammals controls the production of nitric oxide, a cellular signaling agent, by a complex set of reactions that either generate NO or consume it. Much of this control is by iron in vivo. A multi-faceted approach (chemical, biochemical, structural, theoretical) is proposed to obtain a clearer understanding of the iron-NO and the related iron-nitrite interactions central to good health.

铁在生物圈中氮氧化物的化学中扮演着重要的角色。最简单的氮氧化物，NO(一氧化氮)，是一种顺磁性的小分子，它与血红素铁结合，导致各种生物事件，从血管扩张到萤火虫的闪光。血红素铁是错综复杂的参与哺乳动物NO的生物合成和NO的生理信号传递。生物多样性 NO与亚铁血红素结合时的影响引发了关于其身份和化学成分的有趣问题 FeNO部分的性质。相关的亚硝酸阴离子现在被认为在NO中起着关键作用生物化学，可能是哺乳动物体内NO的主要储存形式。有趣的是，肌红蛋白(Mb)和最近有人提出，在低氧条件下，血红蛋白可以作为亚硝酸还原酶，生成在缺氧的环境中没有。在这项拟议的研究中，我们将利用合成、表征、光谱学、小分子分子和蛋白质结晶学、诱变和探索基本问题的理论计算关于NO、亚硝酸盐和相关氮氧化物与生物相关的相互作用的性质亚铁血红素。在特定目标1中，我们将制备一组具有代表性的N碱和硫酸盐连接的亚铁血红素不含配体的模型化合物，并用光谱(IR，EPR，RR，UV-Vis)进行表征，电化学和结晶学。我们将利用DFT计算来提供对 FeNO部分的电子学。MbNO及其突变体也将被检查。在具体目标2中，我们将表征反应途径(无键异构体、与氢给体的反应、无偶联反应、等)在亚铁基团和亚铁血红素模型化合物中可用。亚硝酸盐加合物的血红素模型和 MB(和远端口袋突变体)将在特定目标3中制备和表征，它们将被检查他们将亚硝酸盐转化为NO的能力。与公共健康相关：哺乳动物通过以下方式控制一氧化氮的产生，一氧化氮是一种细胞信号媒介一系列复杂的反应，要么产生NO，要么消耗NO。这种控制在很大程度上是通过体内的铁进行的。一个提出了多方面(化学、生化、结构、理论)的方法，以获得更清晰的了解铁-一氧化氮和相关的铁-亚硝酸盐相互作用对健康至关重要。