Analogues of Zinc Enzymes with Sulfur-Rich Active Sites

描述(申请人提供)：锌被广泛认为是一种元素，对所有形式的生命，特别是人类的生命是必不可少的。因此，锌在许多生物过程(如碳水化合物、脂肪、蛋白质和核酸的合成、调节和降解；基因转录；病毒和免疫现象)中发挥重要作用，是有效生长和发育不可或缺的元素，缺乏锌会导致器官畸形。因此，锌对公众健康的影响最近受到了强烈的重视，从而使锌的生物无机化学成为一个基本和关键的研究领域。这项拟议研究的主要目标是努力阐明锌的生物化学是由300多种酶完成的，每一种基本酶类(氧化还原酶、转移酶、水解酶、裂解酶、异构酶和连接酶)都有代表。要了解锌在生物系统中的许多作用，最重要的是确定锌的化学是如何受到其配位环境的调节的。这项研究的一个具体目标是了解富硫环境中锌的化学结构，该化学结构与肝脏酒精脱氢酶、Ada DNA修复蛋白和5-氨基乙酰丙酸脱水酶等酶有关。例如，锌酶5-氨基酮戊酸脱水酶是形成血红素的早期步骤所必需的，而它被铅灭活是铅对人类有毒的主要原因之一。这项提议的目标将通过研究合成类似物(即模拟锌酶活性部位的结构和功能的小分子)来实现，这些合成类似物是使用硫供体三脚架配体构建的，以模拟与酶中锌配位的蛋白质残基。阐明锌在生物系统中扮演的角色将提供必要的信息，使合理的治疗干预成为可能。

DESCRIPTION (provided by applicant): Zinc is widely recognized as an element that is essential to all forms of life, and especially that of humans. Thus, zinc plays important functions in numerous biological processes (e.g. carbohydrate, lipid, protein and nucleic acid synthesis, regulation and degradation; gene transcription; viral and immune phenomena) and is an indispensable element for effective growth and development, with deficiency resulting in organ malformations. The public health implications of zinc have, therefore, recently been strongly emphasized, thereby making the bioinorganic chemistry of zinc an essential and critical area of investigation. The principal aims of the proposed research are concerned with an effort to elucidate the biological chemistry of zinc that is performed by more than 300 enzymes, with representatives for each of the fundamental enzyme classes (oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases). Paramount to understanding the many roles of zinc in biological systems is a determination of how the chemistry of zinc is modulated by its coordination environment. A specific objective of the research proposed is to provide an understanding of the chemistry of zinc in a sulfur rich environment which is of relevance to enzymes such as liver alcohol dehydrogenase, the Ada DNA repair protein, and 5-aminolevulinate dehydratase. For example, the zinc enzyme 5-aminolevulinate dehydratase is necessary for the early steps of heme formation, and its inactivation by lead is one of the principal reasons why lead is poisonous to humans. The objectives of this proposal will be achieved by investigating synthetic analogues (i.e. small molecules that mimic both the structures and functions of the active sites of zinc enzymes) that are constructed using sulfur donor tripodal ligands to emulate the protein residues that coordinate to zinc in the enzymes. Elucidation of the roles that zinc plays in biological systems will provide the information that is necessary to allow for the possibility of rational therapeutic intervention.