Managing ionic iron: ferri-reduction, ferro-oxidation and iron permeation

描述（由申请人提供）：铁的溶液和氧化还原特性使其成为激活其他惰性底物（包括双氧）的金属假体基的选择，也使离子铁对需氧生物具有细胞毒性。从酵母菌到人类的真核生物必须处理亚铁与二氧的固有反应性和铁在水中的不稳定性；从缺血后组织损伤到神经退行性疾病，铁在人类病理中经常被引用的作用证明了管理离子铁的重要性。我们提出成功抑制铁的生物副反应的铁运输途径有三个基本要素：铁还原、铁氧化和铁通道。通过2型膜蛋白还原酶与提供还原性等效物的胞质吡啶核苷酸或二氢抗坏血酸进行1e-还原，或者在抗坏血酸的情况下通过直接e-转移，使铁成为生物可利用的FeII。在由多铜氧化铁酶催化的4e-还原O2为2H2O的反应中，FeII作为1e-供体的作用抑制了FeII的促氧化潜能，从而绕过了所有的1e-二氧还原产物（ROS）。在这个反应中产生的FeIII通过它的直接转移——它的通道——从铁氧化酶到铁结合蛋白，无论是运输、运输还是储存，都不会被水解。这个代谢途径的一个关键组成部分是铁氧化酶。在项目1中，我们将继续我们富有成效的合作，这些合作对我们理解这些铜氧化酶独特反应性的分子和电子基础做出了重大贡献。在项目2和3中，我们测试了真核生物处理离子铁的基本未知数的具体假设。项目2验证了我们关于铁运输途径的假设，即在所有真菌（包括人类病原体）获取铁的过程中，铁氧化酶反应与渗透反应相结合。项目3将测试还原酶、渗透酶和氧化铁酶如何结合起来支持铁通过血脑屏障运输的模型。许多研究小组对血红素和铁/S簇等铁辅助基团的代谢研究取得了显著进展；离子铁是这些“笼状”铁的前体，是“腐蚀性化学”（伊丽莎白·泰尔）的原因，这种化学是铁和二氧之间关系的特征。了解细胞如何管理这种化学反应将对我们最终阐明许多人类病理的分子基础做出重大贡献，这些病理通常部分归因于离子铁的管理不当。

DESCRIPTION (provided by applicant): The solution and redox properties of iron that make it the metal prosthetic group of choice for the activation of otherwise kinetically inert substrates, including dioxygen, also make ionic Fe cytotoxic to aerobic organisms. Eukaryotes from yeast to humans have to manage ferrous iron's inherent reactivity with dioxygen and ferric iron's instability in water; the oft-cited role of iron in human pathology from post-ischemic tissue damage to neurodegenerative disease is testament to the importance of managing ionic iron. We propose that the Fe- trafficking pathway that succeeds in suppressing Fe's abiologic side-reactions has three essential elements: ferri-reduction, ferro-oxidation, and iron channeling. Ferric iron is made bioavailable - as FeII - by 1e- reduction with cytoplasmic pyridine nucleotide or dihydroascorbic acid supplying the reducing equivalents via a type 2 membrane protein reductase or, in the case of ascorbate by a direct e--transfer. The pro-oxidant potential of the FeII produced is suppressed by its use as 1e- donor in the 4e- reduction of O2 to 2H2O thus by-passing all 1e- dioxygen reduction products (ROS) in a reaction catalyzed uniquely by a multicopper (MCO) ferroxidase. The FeIII generated in this reaction is shielded from hydrolysis by its direct transfer - its channeling - from ferroxidase to ferric iron binding protein, whether or transport, trafficking or storage. A key component of this metabolic pathway is the ferroxidase. In Project 1 we will continue our productive collaborations which have made major contributions to our understanding of the molecular and electronic bases for the unique reactivity of these copper oxidases. In Projects 2 and 3 we test specific hypotheses about fundamental unknowns in the handling of ionic iron by eukaryotes. Project 2 tests our hypothesis about the Fe-trafficking pathway that couples a ferroxidase reaction to a permeation one in the acquisition of iron by all fungi, including human pathogens. Project 3 will test a model for how reductase, permease and ferroxidase combine to support iron trafficking across the blood brain barrier. Outstanding progress has been made by many groups on the metabolism of Fe-prosthetic groups like heme and Fe/S clusters; ionic Fe is the precurser to these "caged" Fe- species and is responsible for the "corrosive chemistry" (Elizabeth Theil) that characterizes the relationship between Fe and dioxygen. An understanding of how cells manage this chemistry would make a significant contribution to our eventual elucidation of the molecular basis for the multitude of human pathologies often attributed in part to mismanaged ionic iron.