METALLOBIOCHEMISTRY OF VANADIUM(V)

目前正在对钒酸盐和其他钒化合物进行评估 人类作为口服胰岛素的仿制药。钒酸盐的络合化学 钒化合物在一定程度上延缓了这些药物的开发。 因为毒性，部分原因是很难确定 哪种化合物是活性物种。最常提出的建议 钒酸盐诱导的胰岛素模拟作用的机制涉及钒酸盐 蛋白质酪氨酸磷酸酶复合体中的酯类。尽管在体内 给与钒酸盐或其他物质时钒酸酯的形成 不稳定的钒化合物，人们对它的活性知之甚少 生物体系中的钒酸酯。这类研究一直受到阻碍。 由于目前关于结构、形成和发展的信息不足 钒酸酯的反应性。这项提案探讨了 在生理条件下测定钒酸盐的化学组成 复合体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 钒酸盐和其他钒化合物的类胰岛素性质 目前正在人体上进行测试。 我们将处理的四个具体目标是： L。测定钒(5)多齿络合物的稳定性 配基。 2.简单氧钒(5)醇盐等的制备和表征 多齿配体的模型络合物。 3.研究了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作用。 4.检测底物、辅因子和抑制物的特异性。 钒酸盐酯。 在《特定目标》一书中描述的研究L将考察 已知的化合物，并开发新的化合物，作为或可能用作 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。 特定目标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密切相关 在此项目中链接，前者是定义系统所必需的 其中钒将作为基态(底物和辅因子)或 作为磷酸酯的过渡态类似物(抑制剂)。是这样的 信息对于评估钒酸根的形成机制至关重要- 诱导类似胰岛素的作用。

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.