MODELING ENZYME DIMETALLIC CENTERS WITH CRYPTATE LIGANDS

本研究计划概述了新型密码配体的合成，该配体包含硫酸盐结合位点，并被设计用于结合两个金属离子在不同但紧密定位的空腔中。直接目的是用这些隐配体制备地铜配合物，以模拟已知存在于细胞色素c氧化酶和氧化亚氮还原酶中的地铜氧化还原中心（CuA位点）。CuA位点的定义性质是可逆电化学和完全离域的CuI-CuII混合价态。后一个特征可能与大约2.5埃单位的短金属-金属分离有关，这被一些人解释为表明直接的金属-金属键相互作用。值得注意的是，这是第一个涉及金属-金属键的生物双金属实体的主张，因此对CuA位点的性质有了详细的理论理解是有保证的。为此，用本文描述的新型含硫酸盐的隐位配体制备二铜配合物将有助于确定功能性CuA位点所需的特征。隐配体的设计允许改变金属供体原子的数量和类型，以及调整不同金属离子结合袋之间的分离。这些方面的差异将允许对它们对CuA站点的重要性进行单独评估。结合这些模型化合物的理论键合分析，这些合成研究将对CuA中心的性质产生更准确的描述。更一般地说，成功地使用密码体结合两个金属离子将使这些配体对其他酶双金属位点的建模具有吸引力。这些密码子可以制备用简单配体难以制备的双核结构。最终，新的双金属结构类型与生物相关类型的供体配体的合成可能提供特定的光谱标准，从而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，可以极大地帮助鉴定新的金属酶的金属中心。

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.