Structural and Functional Studies of Iron Transport and Homeostasis

描述（由申请人提供）：铁运输和代谢疾病是人类痛苦和死亡的最普遍原因之一。全世界有超过十亿人缺铁，导致铁超载（遗传性血色素沉着症）易感性的基因变异在某些人群中非常普遍。作为开发铁缺乏和铁过载治疗方法的必要步骤，我们的长期目标是对铁转运和体内平衡有更深入的生化和结构了解。铁跨膜转运基本上依赖于蛋白质还原酶，蛋白质还原酶将铁转化或维持在正确的氧化态以进行转运。因此，三价铁还原酶和铁还原机制值得进行重大研究，因为它们可以为促进或抑制细胞铁吸收的药物干预提供靶标。我们建议对金属还原酶 Steap 家族进行功能和结构研究相结合，该家族最近与铁转运和稳态有关。这些研究将深入了解转铁蛋白循环中的铁摄取机制，并且似乎也与非转铁蛋白结合的铁摄取机制相关。公共健康相关性：本次资助中提出的研究将调查铁转运和稳态的结构生物学，重点是金属还原酶 Steap 家族。铁稳态缺陷导致铁不足或过量，与一系列疾病状态有关，包括肝硬化、一般癌症和特别是肝细胞癌、糖尿病、贫血和铁超载、中风和各种神经退行性疾病。因此，Steap 蛋白代表了多种人类疾病药物治疗的潜在靶点。

DESCRIPTION (provided by applicant): Diseases of iron transport and metabolism are among the most prevalent causes of human suffering and mortality. Greater than one billion people throughout the world are iron deficient and genetic variants conferring susceptibility to iron overload (hereditary hemochromatosis) are highly prevalent in some populations. As a necessary step in the development of treatments for iron deficiency and iron overload, our long-term goals are to achieve greater biochemical and structural understanding of iron transport and homeostasis. The transport of iron across membranes is substantially dependent upon protein reductases that convert or maintain iron in the correct oxidation state for transport. Ferric reductases and mechanisms of iron reduction are thus worthy of significant investigation as they may provide targets for pharmacological intervention to either promote or inhibit cellular iron uptake. We propose a combination of functional and structural studies on the Steap family of metalloreductases, which have been recently implicated in iron transport and homeostasis. These studies will provide insight into the mechanism of iron uptake in the transferrin-cycle, and appear relevant to the mechanisms of non-transferrin bound iron uptake as well. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant will investigate the structural biology of iron transport and homeostasis, with an emphasis on the Steap family of metalloreductases. Defects in iron homeostasis leading to insufficient or excess iron are relevant to a slew of disease states, including cirrhosis of the liver, cancer in general and hepatocellular carcinoma in particular, diabetes, anemia and iron overload, stroke and various neurodegenerative diseases. For this reason, the Steap proteins represent potential targets of drug therapy in a variety of human disorders.