Flavin-mediated reductive iron mobilization from frog M and Mycobacterial ferritins: impact of their size, charge and reactivities with NADH/O 2,JBIC Journal of Biological Inorganic Chemistry

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Flavin-mediated reductive iron mobilization from frog M and Mycobacterial ferritins: impact of their size, charge and reactivities with NADH/O 2
JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-02-17 , DOI: 10.1007/s00775-021-01850-2
Prashanth Kumar Koochana ₁ , Abhinav Mohanty ₁ , Akankshika Parida ₁ , Narmada Behera ₁ , Pabitra Mohan Behera ₂ , Anshuman Dixit ₂ , Rabindra K Behera ₁

Affiliation

In vitro, reductive mobilization of ferritin iron using suitable electron transfer mediators has emerged as a possible mechanism to mimic the iron release process, in vivo. Nature uses flavins as electron relay molecules for important biological oxidation and oxygenation reactions. Therefore, the current work utilizes three flavin analogues: riboflavin (RF), flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which differ in size and charge but have similar redox potentials, to relay electron from nicotinamide adenine dinucleotide (NADH) to ferritin mineral core. Of these, the smallest/neutral analogue, RF, released more iron (~ three fold) in comparison to the larger and negatively charged FMN and FAD. Although iron mobilization got marred during the initial stages under aerobic conditions, but increased with a greater slope at the later stages of the reaction kinetics, which gets inhibited by superoxide dismutase, consistent with the generation of O₂^∙− in situ. The initial step, i.e., interaction of flavins with NADH played critical role in the iron release process. Overall, the flavin-mediated reductive iron mobilization from ferritins occurred via two competitive pathways, involving the reduced form of flavins either alone (anaerobic condition) or in combination with O₂^∙− intermediate (aerobic condition). Moreover, faster iron release was observed for ferritins from Mycobacterium tuberculosis than from bullfrog, indicating the importance of protein nanocage and the advantages they provide to the respective organisms. Therefore, these structure–reactivity studies of flavins with NADH/O₂ holds significance in ferritin iron release, bioenergetics, O₂-based cellular toxicity and may be potentially exploited in the treatment of methemoglobinemia.

Graphic abstract

Smaller sized/neutral flavin analogue, riboflavin (RF) exhibits faster reactivity towards both NADH and O₂ generating more amount of O₂^∙− and releases higher amount of iron from different ferritins, compared to its larger sized/negatively charged derivatives such as FMN and FAD.

中文翻译：

黄素介导的青蛙 M 和分枝杆菌铁蛋白的还原性铁动员：其大小、电荷和与 NADH/O 2 反应性的影响

在体外，使用合适的电子转移介体对铁蛋白铁进行还原动员已成为模拟体内铁释放过程的可能机制。大自然使用黄素作为重要的生物氧化和氧合反应的电子中继分子。因此，目前的工作利用三种黄素类似物：核黄素（RF）、黄素单核苷酸（FMN）和黄素腺嘌呤二核苷酸（FAD），它们的大小和电荷不同，但具有相似的氧化还原电位，以传递来自烟酰胺腺嘌呤二核苷酸（NADH）的电子到铁蛋白矿物核心。其中，与较大且带负电的 FMN 和 FAD 相比，最小/中性的类似物 RF 释放了更多的铁（约三倍）。虽然铁的动员在有氧条件下的初始阶段受到损害，但在反应动力学的后期阶段以更大的斜率增加，这受到超氧化物歧化酶的抑制，这与原位生成 O ₂ ^{∙ -}一致。第一步，即黄素与 NADH 的相互作用，在铁释放过程中发挥着关键作用。总体而言，黄素介导的铁蛋白还原性铁动员通过两种竞争途径发生，涉及还原形式的黄素单独（厌氧条件）或与 O ₂ ^{∙ -}中间体结合（有氧条件）。此外，观察到结核分枝杆菌铁蛋白的铁释放速度比牛蛙更快，这表明蛋白质纳米笼的重要性及其为各自的生物体提供的优势。因此，黄素与 NADH/O ₂的结构-反应性研究在铁蛋白铁释放、生物能学、基于 O ₂的细胞毒性方面具有重要意义，并且可能在高铁血红蛋白血症的治疗中得到潜在的利用。