MODELING ENZYME DIMETALLIC CENTERS WITH CRYPTATE LIGANDS

用穴状配体模拟酶二金属中心

• 批准号: 6594089
• 负责人: JAMES P DONAHUE
• 金额: $ 4.62万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6594089
• 关键词: binding sites; chemical synthesis; copper; cyclic compound; enzyme model; ligands; metalloenzyme; thiols

This research proposal outlines the synthesis of novel cryptand ligands which incorporate thiolate binding sites and which are designed to bind two metal ions in distinct but closely positioned cavities. The immediate purpose is the preparation of dicopper complexes with these cryptate ligands to simulate the dicopper redox center (CuA site) known to exist in the enzymes cytochrome c oxidase and nitrous oxide reductase. Defining properties of the CuA site are reversible electrochemistry and a fully delocalized CuI-CuII mixed valent state. The latter feature may be related to the short metal-metal separation of approximately 2.5 Angstrom units, which has been interpreted by some as indicating a direct metal-metal bonding interaction. Significantly, this claim is the first for a biologically occurring dimetallic entity involving a metal-metal bond, and as such a detailed theoretical understanding of the nature of the CuA site is warranted. Pursuant to this end, the preparation of dicopper complexes with the novel thiolate-containing cryptand ligands described herein will help to ascertain the features requisite for a functional CuA site. The cryptate ligand design is such as to permit variation in the number and type of donor atoms to the metals as well as adjustment of the separation between the distinct metal ion binding pockets. Variations in each of these aspects will permit separate assessment of their importance to the CuA site. Coupled with a theoretical bonding analysis of these model compounds, these synthetic studies will yield a more accurate description of the nature of the CuA center. More generally, the successful use of cryptands to bind two metal ions will make these ligands attractive for modeling other enzyme dimetallic sites. These cryptands may permit preparation of dinuclear structures which are otherwise difficult to prepare with simple ligands. Ultimately, the synthesis of new dimetallic structure types with biologically relevant types of donor ligands may provide specific spectroscopic criteria whereby the recognition of such structure in new metalloenzymes will be facilitated. Identification of the metal centers in new metalloenzymes is greatly aided by comparison to the properties of simple inorganic analogues.

这项研究计划概述了新型穴状配体的合成，其中包括硫醇结合位点，并被设计为在不同但位置接近的空腔中结合两个金属离子。 直接目的是制备具有这些穴状配体的二铜络合物以模拟已知存在于酶细胞色素c氧化酶和一氧化二氮还原酶中的二铜氧化还原中心（CuA位点）。 定义性质的CuA网站是可逆的电化学和完全离域的CuI-CuII混合价态。 后一特征可能与约2.5埃单位的短金属-金属分离有关，这已被一些人解释为指示直接金属-金属键合相互作用。值得注意的是，这一说法是第一个涉及金属-金属键的生物学双金属实体，因此有必要对CuA位点的性质进行详细的理论理解。根据这一目的，用本文所述的新型含硫醇盐穴状配体制备双铜络合物将有助于确定功能性CuA位点所需的特征。 穴状化合物配体设计允许金属的供体原子的数量和类型的变化以及不同金属离子结合口袋之间的间隔的调节。 这些方面的变化将允许单独评估其对CuA场地的重要性。再加上这些模型化合物的理论成键分析，这些合成研究将产生一个更准确的描述的性质的CuA中心。 更一般地，穴状配体结合两个金属离子的成功使用将使这些配体对模拟其他酶双金属位点具有吸引力。 这些穴状配体可以允许制备双核结构，否则难以用简单的配体制备。 最后，与生物相关类型的供体配体的新的双金属结构类型的合成可以提供特定的光谱标准，由此将促进在新的金属酶中识别这种结构。通过与简单的无机类似物的性质进行比较，可以大大有助于新金属酶中金属中心的鉴定。