SYNTHETIC ANALOGUES OF ZINC ENZYMES

锌酶的合成类似物

• 批准号: 6628814
• 负责人: GERARD PARKIN
• 金额: $ 25.69万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628814
• 关键词: X ray crystallography; active sites; alcohol dehydrogenase; alkyltransferase; chemical structure function; chemical synthesis; enzyme model; enzyme substrate complex; ligands; metalloendopeptidases; metalloenzyme; nuclear magnetic resonance spectroscopy; porphobilinogen synthase; receptor binding; stereochemistry; synthetic enzyme; zinc

DESCRIPTION: (Adapted from applicant's abstract) Zinc is widely recognized as being essential to all forms of life, and in particular that of humans. 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. Likewise, matrix metalloproteinases are an extremely important group of zinc enzymes that are involved in extracellular degradation and participate in embryonic development, wound healing, bone and growth development, and other physiological remodeling processes. However, despite the beneficial aspects of matrix metalloproteinases during normal biological processes, their activity in pathological situations when extracellular degradation is not required may have a most detrimental influence. In this regard, undesired matrix metalloprotease activity has been linked to a variety of cancers (including lung, breast, and colon cancer), arthritis, multiple sclerosis, and Alzheimer's disease. Zinc has also been reported to have beneficial therapeutic and preventative effects on infectious diseases and zinc gluconate lozenges have been proposed to shorten the length of the common cold in adults. The public health importance of zinc has recently been strongly emphasized, thereby making the bioinorganic chemistry of zinc an essential and critical area of investigation. In order to understand the many roles of zinc in biological systems, it is first absolutely essential to understand how the chemistry of zinc is modulated by its coordination environment. The intent of this proposal is to obtain a thorough understanding of the bioinorganic chemistry of zinc by investigating synthetic analogues that mimic both the structure and function of the active sites of zinc enzymes. This objective will be achieved by using specially constructed tripod ligands to afford synthetic analogues that will be amenable to structural, spectroscopic and mechanistic studies. During the previous grant period significant progress was made toward the stated goals. Specifically, three accomplishments merit further comment. Using [TptBu,Me]ZnX complexes, the group successfully prepared the first pair of Zn-hydroxide, Zn-aqua complexes. Reversible protonation of a Zn-hydroxide was demonstrated using a novel Bronsted acid to overcome problems of lability of the water ligand. With these two complexes in hand, differential reactivity toward carbon dioxide was demonstrated. Second, the group has made major progress in the preparation of ligands (and the corresponding metal complexes) that provide mixed donors, e.g. [N2O] or [N2S]. Third, the reactivity modeling of LADH has progressed enormously. Zinc alkoxide derivatives have been prepared and structurally authenticated. Alcohol exchange reactions have allowed for the extraction of thermodynamic parameters. Finally, and most notably, the zinc alkoxides react with aldehyde to yield products consistent with "hydride" transfer; the key step in LADH catalysis. As another marker of excellent productivity, eleven papers have either been published or submitted in the previous grant period.

描述：（改编自申请人的摘要）锌被广泛认为是 对于所有生命形式，特别是人类来说，都是至关重要的。为了 例如，锌酶 5-氨基乙酰丙酸脱水酶对于 血红素形成的早期步骤，铅使其失活是其中之一 铅对人体有毒的主要原因。同样，矩阵 金属蛋白酶是一组极其重要的锌酶， 参与细胞外降解并参与胚胎发育， 伤口愈合、骨骼和生长发育以及其他生理重塑 流程。然而，尽管基质金属蛋白酶具有有益的方面 在正常的生物过程中，它们在病理情况下的活动 当不需要细胞外降解时可能会产生最有害的影响 影响。在这方面，不需要的基质金属蛋白酶活性已被 与多种癌症（包括肺癌、乳腺癌和结肠癌）有关， 关节炎、多发性硬化症和阿尔茨海默病。锌也被 据报道对传染病具有有益的治疗和预防作用 已提出使用葡萄糖酸锌含片来缩短长度 成人普通感冒。最近，锌对公共卫生的重要性 被大力强调，从而使锌的生物无机化学成为 调查的基本和关键领域。为了了解很多 锌在生物系统中的作用，首先绝对重要的是 了解锌的化学性质是如何通过其配位来调节的 环境。本提案的目的是为了获得透彻的了解 通过研究合成类似物来研究锌的生物无机化学 模仿锌酶活性位点的结构和功能。这 目标将通过使用特殊构造的三脚配体来实现 提供适合结构、光谱的合成类似物 和机理研究。 在上一个资助期间，在以下方面取得了重大进展： 既定目标。具体来说，三项成就值得进一步评论。使用 [TptBu,Me]ZnX配合物，课题组成功制备出第一对 氢氧化锌、水合锌络合物。氢氧化锌的可逆质子化为 证明使用新型布朗斯台德酸可以克服不稳定的问题 水配体。有了这两种复合物，不同的反应性 证明了对二氧化碳的影响。二、集团取得重大成果 配体（及相应金属配合物）制备进展 提供混合捐助者，例如[N2O] 或 [N2S]。三、反应性建模 LADH 已取得巨大进展。醇锌衍生物的制备 并经过结构验证。醇交换反应允许 热力学参数的提取。最后，也是最值得注意的是，锌 醇盐与醛反应生成与“氢化物”一致的产物 转移; LADH催化的关键步骤。作为优秀的另一个标志 已发表或提交论文 11 篇 之前的资助期。