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 对所有生命形式都是必不可少的，尤其是人类。为 例如，锌酶5-氨基乙酰丙酸酯酶是必需的， 血红素形成的早期步骤，其失活的铅是一个 铅对人体有毒的主要原因。同样，矩阵 金属蛋白酶是锌酶中非常重要的一组， 参与细胞外降解并参与胚胎发育， 伤口愈合、骨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的有益方面， 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， 影响力的社会在这方面，不希望的基质金属蛋白酶活性已经被发现。 与多种癌症有关（包括肺癌、乳腺癌和结肠癌）， 关节炎、多发性硬化症和老年痴呆症。锌也是 据报道，对感染性疾病具有有益的治疗和预防作用， 疾病和葡萄糖酸锌锭剂已被提出来缩短长度 成人的普通感冒。锌对公众健康的重要性最近 被强烈强调，从而使锌的生物无机化学， 重要和关键的调查领域。为了了解许多 锌在生物系统中的作用，首先绝对必要的是， 了解锌的化学是如何通过其配位调节的 环境这一建议的目的是为了获得一个彻底的理解， 通过研究合成类似物来研究锌的生物无机化学， 模拟锌酶活性位点的结构和功能。这 通过使用特殊构造的三脚架配体来实现该目的， 提供合成的类似物，将服从结构，光谱， 机械研究。 在上一个赠款期间， 陈述的目标。具体而言，有三项成就值得进一步评论。使用 [TptBu，Me]ZnX配合物，该小组成功地制备了第一对 锌氢氧化物、锌水络合物。可逆质子化的锌氢氧化物是 证明了使用新的布朗斯台德酸来克服 水配体。有了这两种复合物， 向二氧化碳的转化。第二，集团已取得重大进展。 配体（及其金属配合物）的制备进展 其提供混合供体，例如[N2 O]或[N2 S]。第三，反应性建模 已经取得了巨大的进步。制备了锌醇盐衍生物 并经过结构验证。酒精交换反应使得 热力学参数的提取最后，也是最值得注意的， 醇盐与醛反应生成与“氢化物”一致的产物 转移是LADH催化的关键步骤。作为另一个优秀的标志 生产力，11篇论文已发表或提交， 上一个补助期。