METALLOBIOCHEMISTRY OF VANADIUM(V)

钒(V)的金属生物化学

• 批准号: 2684892
• 负责人: DEBBIE Catharina CRANS
• 金额: $ 15.57万
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2684892
• 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.

钒酸盐和其他钒化合物目前正在评估中， 作为口服胰岛素模拟药物。钒酸盐的复杂化学 钒化合物在一定程度上延缓了这些药物的开发 因为毒性，部分原因是难以确定 该化合物是活性物质。最常见的建议 钒酸盐诱导的胰岛素模拟作用的机制涉及钒酸盐 蛋白酪氨酸磷酸酶复合物中酯。尽管体内 在施用钒酸盐或其他物质时形成钒酸酯 不稳定的钒化合物，很少有人知道的活动， 生物系统中的钒酸酯。 这类研究一直受到阻碍 由于目前有关结构、形成和 钒酸酯的反应性。本提案探讨了 钒酸盐化学在生理条件下，以确定 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，这些研究与理解 钒酸盐和其它钒化合物的胰岛素模拟性质 目前正在人体试验中。 我们要达到的四个具体目标是： L.测定了多齿钒（+5）配合物的不稳定性 配体。 2.制备和表征简单的氧钒（+5）醇盐和其他 多齿配体的模型配合物。 3.研究钒氧酸盐自交换反应的机理和动力学 和与简单有机配体络合。 4.为了检查底物，辅因子和抑制剂的特异性， 钒酸酯 具体目标1中描述的研究将检查 已知的化合物和开发新的化合物，这些化合物或可以用作 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为酶底物， 辅因子或抑制剂。化学和生物化学研究与 在这个项目中，前者是必要的，以确定系统 其中钒将作为基态（底物和辅因子），或者 作为磷酸酯的过渡态类似物（抑制剂）。等 信息对于评估钒酸盐形成机制至关重要， 诱导的胰岛素样作用。