Bou-Abdallah Fadi, Paliakkara John J, Melman Galina, Melman Artem
Department of Chemistry, State University of New York at Potsdam, Potsdam, NY 13676, USA.
Department of Chemistry & Biomolecular Science, Clarkson University, Potsdam, NY 13699, USA.
Pharmaceuticals (Basel). 2018 Nov 5;11(4):120. doi: 10.3390/ph11040120.
Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo. In contrast, there is a wide spread belief that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin, and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms, involving physiological reducing agents and/or cellular reductases, contribute to the release of iron from ferritin. In vitro iron mobilization from ferritin can be achieved using different reducing agents, capable of easily reducing the ferritin iron core, to produce soluble ferrous ions that are subsequently chelated by strong iron(II)-chelating agents. Here, we review our current understanding of iron mobilization from ferritin by various reducing agents, and report on recent results from our laboratory, in support of a mechanism that involves a one-electron transfer through the protein shell to the iron mineral core. The physiological significance of the iron reductive mobilization from ferritin by the non-enzymatic FMN/NAD(P)H system is also discussed.
铁蛋白是由两种不同亚基类型，即H（重链）和L（轻链）组成的高度保守的超分子蛋白质纳米结构。这两种亚基共同组装成一个24亚基的杂聚物，具有组织特异性分布，形成壳状蛋白质结构，其中数千个铁原子作为可溶性无机铁核心储存。在体外（或无细胞系统中），尽管铁如何在体内加载到蛋白质中仍不清楚，但亚铁氧化和矿物核心形成的机制已得到广泛研究。相比之下，人们普遍认为铁从铁蛋白中动员的主要途径涉及铁蛋白的溶酶体蛋白水解降解以及铁矿物核心的溶解。然而，涉及生理还原剂和/或细胞还原酶的其他辅助铁动员机制是否有助于铁从铁蛋白中释放仍不清楚。使用不同的还原剂可以实现铁蛋白在体外的铁动员，这些还原剂能够轻松还原铁蛋白铁核心，产生可溶性亚铁离子，随后被强亚铁螯合剂螯合。在这里，我们综述了目前对各种还原剂从铁蛋白中动员铁的理解，并报告了我们实验室的最新结果，以支持一种涉及通过蛋白质外壳向铁矿物核心进行单电子转移的机制。还讨论了非酶FMN/NAD(P)H系统从铁蛋白中进行铁还原动员的生理意义。
