MECHANISM OF IRON REMOVAL FROM TRANSFERRIN BY AMINOPHOSP

铁代谢的难题之一是细胞在铁代谢中的作用机制。 如此有效地去除铁离子从强大的铁螯合 转铁蛋白 铁从转铁蛋白中释放的机制是 也与开发更有效的药物高度相关， 治疗折磨β-地中海贫血患者的铁超负荷， 镰状细胞性贫血 铁向低分子量配体的释放已经被证实。 研究了几种类型的配体，包括多磷酸盐， 异羟肟酸，氨基酸和儿茶酚，和冲突的机制， 提出如 本项目涉及系统的除铁动力学研究， 一系列氨基膦酸和酚类配体。 一个主要目标 这项研究的目的是区分两个最突出的建议， 去除铁的机制。 这涉及到对 反应速率作为竞争的 配体和碳酸氢根，以及活化参数的确定 每个配体的速率常数。 在饱和动力学 的铁去除率的双曲线依赖于 将建立配体的浓度，并且伪一阶 速率常数将被确定为在高配体的速率限制步骤 浓度的 速率常数也将被确定为铁去除 来自N-末端和C-末端单（铁）转铁蛋白。 还将记录铁-转铁蛋白与 单齿配体如磷酸根、苯酚和乙酸根，以表征 任何混合配体络合物，其可以在不存在 将发生显著量铁去除。

One of the puzzles of iron metabolism is the mechanism by which cells are so effective at removing ferric ion from the powerful iron chelating protein transferrin. The mechanism of iron release from transferrin is also highly relevant to the development of a more effective drug for the treatment of iron overload which afflicts victims of Beta-thalassemia and sickle cell anemia. Iron release to low molecular weight ligands has been studied for several types of ligands, including polyphosphates, hydroxamates, amino acids, and catechols, and conflicting mechanisms have been proposed. This project involves a systematic study of the kinetics of iron removal by a series of aminophosphonic acid and phenolic ligands. A major objective of this study is to distinguish between the two most prominent proposed mechanisms for iron removal. This involves a full evaluation of the reaction rate as a function of the concentration of both the competing ligand and bicarbonate, and the determination of the activation parameters for the rate constants for each ligand. In cases where saturation kinetics are observed, the hyperbolic dependence of the rate of iron removal on the concentration of the ligand will be established, and pseudo first order rate constants will be determined for the rate limiting step at high ligand concentrations. Rate constants will also be determined for iron removal from both N-terminal and C-terminal mono(ferric)transferrin. Spectra will also be recorded for mixtures of ferric-transferrin with monodentate ligands such as phosphate, phenol, and acetate to characterize any mixed-ligand complex which may form under conditions where no significant amount of iron removal will occur.