Synthetic Modeling of Copper Protein Active Sites

铜蛋白活性位点的综合建模

• 批准号: 7924288
• 负责人: WILLIAM B Tolman
• 金额: $ 3.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924288
• 关键词: Active Sites; Address; Anabolism; Binding; Biological Assay; Biological Process; Biology; Chemicals; Chemistry; Complex; Copper; Data; Decarboxylation; Dioxygen; Disease; Electronics; Electrons; Encapsulated; Enzymes; Glean; Goals; Health; Histidine; Homeostasis; Hormones; Human; Hydroxylation; Ions; Iron; Keto Acids; Knowledge; Laboratories; Lead; Life; Ligands; Metalloproteins; Metals; Methane hydroxylase; Mixed Function Oxygenases; Modeling; Molecular; Molecular Weight; Mono-S; Nature; Neurotransmitters; Nitrites; Nitrogen; Nitrogen Oxides; Nitrous Oxide; Oxidants; Oxidases; Oxidation-Reduction; Oxygen; Particulate; Pathway interactions; Play; Process; Production; Property; Protein Binding; Proteins; Public Health; Reaction; Reagent; Research; Respiration; Respiratory Process; Role; Route; Side; Site; Structure; Structure-Activity Relationship; Sulfides; Sulfur; Testing; Work; analog; biological systems; catalyst; chemical reaction; design; electronic structure; enzyme model; enzyme structure; greenhouse gases; insight; interest; microbial; nitrous oxide reductase; novel; oxidation; oxygen compounds; peptide hormone; protein structure function; public health relevance; small molecule

DESCRIPTION (provided by applicant): Copper plays a key role in numerous environmentally and biologically important processes, particularly when encapsulated within enzymes that are widely distributed in Nature. The copper ions in the active sites of enzymes perform a variety of significant functions, including the binding and activation of dioxygen (O2) for effecting metabolically significant chemical reactions and the reduction of oxidized nitrogen-containing compounds like nitrite and nitrous oxide (N2O) during microbial respiratory processes important within the global nitrogen cycle. Despite extensive research, many questions remain unanswered concerning the detailed molecular level pathways of these processes. The research described herein addresses some of these questions through the synthetic modeling approach. In this approach, low molecular weight complexes designed to replicate aspects of copper enzyme active site structure and function are characterized and their reactivity studied. The goals are to develop detailed understanding of geometries, electronic structures, bonding, and reaction mechanisms relevant to the biological systems. In particular, the research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved in the binding and activation of O2 and N2O. This objective will be addressed through three specific aims: (1) Dioxygen Activation at Monocopper Sites, (2) Dioxygen Activation at Multicopper Sites, and (3) Copper-Sulfur Chemistry for Modeling the CuZ Site of Nitrous Oxide Reductase. In aims (1) and (2), synthetic analogs of highly reactive mono- and multicopper oxidizing species will be prepared in order to evaluate their possible role in enzymes that bind and activate O2. In aim (3), new multicopper(I)-sulfide models of the unusual tetracopper-sulfide cluster (CuZ) found in an environmentally important enzyme, nitrous oxide reductase, will be synthesized and their reactivity with N2O will be studied. In addition to aspiring to a deep understanding of copper enzyme structure/function relationships, the proposed work is aimed at developing novel copper chemistry of fundamental significance. PUBLIC HEALTH RELEVANCE: The research aims to provide detailed understanding of the fundamental chemistry underlying the function of an important subset of copper-containing enzymes involved in the binding and activation of O2 and N2O. The dioxygen-activating enzymes are involved in a plethora of important biological processes central to life, including respiration, metal ion homeostasis (the disruption of which causes disease), and the production of important organic metabolites, hormones, and neurotransmitters essential to human health. The reduction of N2O by the microbial enzyme nitrous oxide reductase converts this greenhouse gas to inert N2 in a process recognized to be a critical component of the global nitrogen cycle and thus directly relevant to public health.

描述（由申请人提供）：铜在许多环境和生物学上重要的过程中起关键作用，尤其是当封装在自然界中广泛分布的酶中时。酶的活性位点中的铜离子执行多种重要功能，包括二氧化基因（O2）的结合和激活，以实现代谢上具有重要意义的化学反应的作用，以及在小动物呼吸器过程中，在整体氮气中，在微生物呼吸器过程中，含氮和二氮（N2O）（N2O）（N2O）的氧化化合物的减少。尽管进行了广泛的研究，但关于这些过程的详细分子水平途径，许多问题仍然没有解决。本文描述的研究通过合成建模方法解决了其中一些问题。在这种方法中，旨在复制铜酶活性位点结构和功能方面的低分子量复合物的表征，并研究了它们的反应性。目标是对与生物系统相关的几何，电子结构，粘结和反应机制进行详细的了解。特别是，该研究旨在详细了解与O2和N2O的结合和激活有关的重要子集的重要子集的基本化学。该目标将通过三个特定目的来解决：（1）单尾部位点的二氧化激活，（2）多掌位的二氧化物激活，以及（3）（3）铜硫化学，用于建模一硝酸氧化物还原酶的CUZ位点。在AIM（1）和（2）中，将准备高反应性单磷酸物种和多功能氧化物种的合成类似物，以评估它们在结合和激活O2的酶中的可能作用。在AIM（3）中，将合成在环境重要的酶，一硝基氧化物还原酶中发现的不寻常的四硫化物 - 硫化物簇（CUZ）的新的多能（I） - 硫化物模型，并将研究其与N2O的反应性。除了渴望深入了解铜酶结构/功能关系外，拟议的工作还旨在发展具有基本意义的新型铜化学。公共卫生相关性：该研究旨在详细了解对O2和N2O的结合和激活涉及的重要含铜酶的重要子集的基本化学反应。二氧化激活酶参与了许多重要生命中心的重要生物学过程，包括呼吸，金属离子稳态（导致疾病的破坏）以及重要的有机代谢产物，激素和神经递质对人类健康至关重要。微生物酶一氧化二氮还原酶减少N2O，将这种温室气体转化为惰性N2，在公认是全球氮循环的关键成分的过程中，因此与公共卫生直接相关。