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性质使其成为活化其他动力学惰性底物（包括分子氧）的金属辅基，也使离子铁对需氧生物体具有细胞毒性。从酵母到人类的真核生物必须管理亚铁与分子氧的固有反应性和三价铁在水中的不稳定性;铁在从缺血后组织损伤到神经退行性疾病的人类病理学中的经常引用的作用证明了管理离子铁的重要性。我们提出，成功地抑制铁的非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。三价铁是生物可利用的-作为Fe II-通过1 e-还原与细胞质吡啶核苷酸或二氢抗坏血酸提供的还原当量通过2型膜蛋白还原酶，或在抗坏血酸的情况下，通过直接的e-转移。通过在O2至2 H2O的4 e-还原中用作1 e-供体，从而在由多铜（MCO）亚铁氧化酶唯一催化的反应中绕过所有1 e-双氧还原产物（ROS），抑制了所产生的Fe II的促氧化剂潜力。该反应中产生的FeIII通过其从铁氧化酶到三价铁结合蛋白的直接转移（其通道作用）而免受水解，无论是运输、运输还是储存。这种代谢途径的一个关键组成部分是铁氧化酶。在项目1中，我们将继续进行富有成效的合作，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，我们测试了关于真核生物处理离子铁的基本未知数的特定假设。项目2测试了我们关于铁运输途径的假设，该途径将铁氧化酶反应与所有真菌（包括人类病原体）获取铁的渗透反应结合起来。项目3将测试还原酶、通透酶和铁氧化酶联合收割机如何支持铁穿过血脑屏障的模型。许多研究小组在铁辅基（如血红素和Fe/S簇）的代谢方面取得了显著的进展;离子Fe是这些“笼状”Fe物种的替代物，并负责表征Fe和分子氧之间关系的“腐蚀性化学”（Elizabeth Theil）。了解细胞如何管理这种化学物质将对我们最终阐明人类多种病理学的分子基础做出重大贡献，这些病理学通常部分归因于管理不当的离子铁。

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.