Bradley Justin M, Carter Aiden M, Bugg Zinnia, Andrews Simon C, Le Brun Nick E
Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
School of Biological Sciences, University of Reading, Whiteknights, Reading, RG6 6EX, UK.
Angew Chem Int Ed Engl. 2025 Aug 18;64(34):e202511340. doi: 10.1002/anie.202511340. Epub 2025 Jun 25.
Iron is in an essential micronutrient in living systems. However, it is also potentially toxic and so the concentration of chelatable iron within cells is tightly regulated to prevent catalytic formation of harmful reactive oxygen species (ROS). Ferritins play a key role in iron homeostasis by storing excess iron as an insoluble ferric mineral within the protein. When bacterial cells become iron deficient, this store may be accessed by reduction/solubilisation of the iron. Bacterioferritins utilise heme, bound at an inter-subunit site, to support electron transfer to the stored mineral. Electrons for heme reduction are shuttled from NADPH via Bfd, a [2Fe-2S] cluster-containing ferredoxin. This raises the paradox that the synthesis of an iron-dependent protein co-factor is required under conditions of iron-deficiency so that stored iron can be utilised. Here, we show that exposure of Bfd to ROS suppresses the capacity of the protein to stimulate iron release from bacterioferritin. We propose that reliance of iron release on Bfd evolved to ensure that chelatable iron levels do not increase under oxidative stress conditions. Thus, the Bfd iron-sulfur cluster functions as a "biological fuse" in providing a fail-safe that immediately halts iron release once ROS accumulate to damaging concentrations.
铁是生命系统中一种必需的微量营养素。然而，它也具有潜在毒性，因此细胞内可螯合铁的浓度受到严格调控，以防止有害活性氧（ROS）的催化形成。铁蛋白通过将过量的铁作为不溶性铁矿物储存在蛋白质中，在铁稳态中发挥关键作用。当细菌细胞缺铁时，这种储存的铁可通过铁的还原/溶解来获取。细菌铁蛋白利用结合在亚基间位点的血红素，来支持电子向储存矿物的转移。用于血红素还原的电子从NADPH通过Bfd穿梭，Bfd是一种含[2Fe-2S]簇的铁氧还蛋白。这就产生了一个矛盾，即在缺铁条件下需要合成一种铁依赖性蛋白质辅因子，以便能够利用储存的铁。在这里，我们表明Bfd暴露于ROS会抑制该蛋白质刺激细菌铁蛋白释放铁的能力。我们提出，铁释放对Bfd的依赖性进化是为了确保在氧化应激条件下可螯合铁水平不会增加。因此，Bfd铁硫簇起到“生物保险丝”的作用，一旦ROS积累到有害浓度，就立即停止铁释放，提供一种故障安全机制。
