METALLOBIOCHEMISTRY OF VANADIUM(V)

钒(V)的金属生物化学

• 批准号: 2392061
• 负责人: DEBBIE Catharina CRANS
• 金额: $ 14.98万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2392061
• 关键词: chemical models; chemical structure function; electron spin resonance spectroscopy; esters; ethanolamines; glucose 6 phosphate dehydrogenase; imidazole; ligands; metal complex; model design /development; molecular dynamics; nuclear magnetic resonance spectroscopy; transaldolase /transketolase; ultraviolet spectrometry; vanadium

Vanadate and other vanadium compounds are currently being evaluated in humans as oral insulin mimetic drugs. The complex chemistry of vanadate and vanadium compounds has delayed the development of these drugs in part because of toxicity and in part because of the difficulty in determining which compound is the active species. The most commonly proposed mechanism for vanadate-induced insulin mimetic action involves a vanadate ester in a protein tyrosine phosphatase complex. Despite the in vivo formation of vanadate esters upon administration of vanadate or other labile vanadium compounds, little is known about the activities of vanadate esters in biological systems. Such studies have been hampered by the current inadequate information concerning structure, formation and reactivity of vanadate esters. This proposal explores the fundamental chemistry of vanadate under physiological conditions to determine what types of complexes form and how these compounds interact with proteins. Accordingly, these studies are of direct relevance to understanding the insulin mimetic properties of vanadate and other vanadium compounds currently being tested in humans. The four specific aims we will address are: l. To determine the lability of vanadium(+5) complexes of polydentate ligands. 2. To prepare and characterize simple oxovanadium(+5) alkoxides and other model complexes of multidentate ligands. 3. To examine the mechanism and dynamics of oxovanadate's self-exchange and complexation with simple organic ligands. 4. To examine the substrate, cofactor and inhibitor specificity of vanadate esters. The studies described in Specific Aim l will examine the lability of known compounds and develop new compounds that are, or could be, used as potential insulin mimetic agents. Specific Aims 2 and 3 will characterize the kinds of compounds that can form under physiological conditions. Specific Aim 4 will determine if these compounds are enzyme substrates, cofactors or inhibitors. The chemical and biochemical studies are closely linked in this project, the former being necessary to define the systems in which vanadium will act as a ground-state (substrate and cofactor) or as a transition-state analog (inhibitor) of phosphate esters. Such information is essential to evaluate mechanisms contributing to vanadate- induced insulin-mimetic action.

目前正在评估钒酸盐和其他钒化合物 人类作为口服胰岛素模拟药物。钒酸盐的复杂化学性质 钒化合物部分推迟了这些药物的开发 因为毒性，部分是因为难以确定 哪种化合物是活性物质。最常提出的 钒酸盐诱导胰岛素模拟作用的机制涉及钒酸盐 蛋白质酪氨酸磷酸酶复合物中的酯。尽管体内 给予钒酸盐或其他物质后形成钒酸酯 不稳定的钒化合物，人们对其活性知之甚少 生物系统中的钒酸酯。 此类研究受到阻碍 由于目前有关结构、形成和 钒酸酯的反应活性。该提案探讨了基本 生理条件下钒酸盐的化学性质以确定什么 复合物的类型以及这些化合物如何与蛋白质相互作用。 因此，这些研究对于理解 钒酸盐和其他钒化合物的胰岛素模拟特性 目前正在人体中进行测试。 我们将解决的四个具体目标是： 湖确定多齿钒(+5)配合物的不稳定性 配体。 2. 简单氧钒(+5)醇盐等的制备和表征 多齿配体的模型复合物。 3. 考察氧钒酸盐自交换的机理和动力学 以及与简单有机配体的络合。 4. 检查底物、辅因子和抑制剂的特异性 钒酸酯。 具体目标 l 中描述的研究将检验以下因素的不稳定性： 已知化合物并开发新化合物，这些化合物可以或可以用作 潜在的胰岛素模拟剂。具体目标 2 和 3 将描述 在生理条件下可以形成的化合物的种类。 具体目标 4 将确定这些化合物是否是酶底物， 辅因子或抑制剂。化学和生物化学研究密切 在这个项目中链接，前者对于定义系统是必要的 其中钒将充当基态（底物和辅因子）或 作为磷酸酯的过渡态类似物（抑制剂）。这样的 信息对于评估促进钒酸盐的机制至关重要 诱导胰岛素样作用。