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 对各种形式的生活，尤其是人类至关重要。为了 例如，锌酶5-氨基甲基乙酸酯脱氢酶是必要的 血红素形成的早期步骤及其铅的失活是 铅对人有毒的主要原因。同样，矩阵 金属蛋白酶是一个极为重要的锌酶， 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 过程。但是，尽管基质金属蛋白酶有益 在正常的生物过程中，它们在病理情况下的活性 当不需要细胞外降解时，可能会有最有害的 影响。在这方面，不希望的基质金属蛋白酶活性已经 与各种癌症（包括肺，乳腺癌和结肠癌）有关， 关节炎，多发性硬化症和阿尔茨海默氏病。锌也已经 据报道对感染性具有有益的治疗和预防作用 已经提出了疾病和葡萄糖酸盐lozenges来缩短长度 成人普通感冒。锌的公共健康重要性最近 强烈强调，从而使锌的生物无机化学 调查的基本和关键领域。为了了解许多 锌在生物系统中的作用，首先是至关重要的 了解锌的化学如何通过其协调来调节 环境。该提议的目的是获得透彻的理解 通过研究合成类似物的生物无机化学 模仿锌酶的活性位点的结构和功能。这 将通过使用特殊构造的三脚架配体来实现目标 提供合成类似物，可以适应结构，光谱镜 和机械研究。 在上一个赠款期间，取得了重大进展 陈述目标。具体来说，三个成就值得进一步评论。使用 [tptbu，我] Znx综合体，该小组成功准备了第一对 Zn-Hydroxide，Zn-Aqua综合体。 Zn-羟基的可逆质子化为 使用新型的布朗斯特酸证明，以克服 水配体。手里拿着这两个复合物，反应性差异 证明了朝向二氧化碳。其次，该小组成为了专业 配体制备的进展（以及相应的金属络合物） 提供混合捐助者，例如[N2O]或[N2S]。第三，反应性建模 Ladh的进步巨大。已经制备了千氧化锌衍生物 并在结构上验证。酒精交换反应允许 提取热力学参数。最后，最值得注意的是锌 烷氧与醛反应，产生与“氢化物”一致的产品 转移; LADH催化的关键步骤。作为优秀的另一个标记 生产力，十一篇论文已发表或提交 以前的赠款期。