Abstract
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.
Highlights
Iron is an essential element required for virtually all living organisms and is involved in numerous biological reactions including respiration, oxygen transport, electron transfer, oxidative metabolism, deoxyribonucleotide synthesis, and gene regulation [1,2]
Because a significant concentration of flavins is commonly found in the cytosol of living cells, reduced flavins are possible candidates for the hypothetical reductive mobilization of iron cations from intact ferritins [30,31], Pharmarceeauctitciaolsn20c1a8n, 11b, e120catalyzed by NAD(P)H:flavin oxidoreductase [30], or can proceed without4 of 14 enzymatic catalysis at higher concentrations of flavins and NADH [42]
The inability of agarose-immobilized FMNH2 to induce reductive mobilization of iron cations from horse spleen ferritin [31], was considered as proof of the inability of FMNH2 to diffuse toPthharempacreouttiecainls’2s0i1n8,te11r,io12r0, and that ferritin iron reduction reactions can only proceed through FMN6Hof214 diffusion into ferritin
Summary
Iron is an essential element required for virtually all living organisms and is involved in numerous biological reactions including respiration, oxygen transport, electron transfer, oxidative metabolism, deoxyribonucleotide synthesis, and gene regulation [1,2]. In living cells iron(III) cations produced via Fenton reaction can be rapidly reduced back to iron(II) cations, leading to a continuous cycle of hydroxyl radicals (HO ) production To avoid this dangerous cycle of hydroxPyhalrmraacdeuitcicaallss20f1o8r, m11,axtion, the concentration of labile iron is regulated by a strict contro lofo1f3 the rates of ironiruopntiaskreegaunladtemd boybailisztraicttiocnonitnroilroofnthterarnatseps oorftiraonndupsttaokreaganedpmrootbeiilnizsa.tiWonhinileirocneltlrualnasrpoirrot nantdrafficking is suggsetosrtaegde tporootcecinusr. Because a significant concentration (several mM) of flavins is commonly found in the cytosol of living cells, reduced flavins are possible candidates for the hypothetical reductive mobilization of iron cations from intact ferritins [30,31], Pharmarceeauctitciaolsn20c1a8n, 11b, e120catalyzed by NAD(P)H:flavin oxidoreductase [30], or can proceed without of 14 enzymatic catalysis at higher concentrations of flavins and NADH [42]. Repri2n,t2e′-dbiwpyitrhidpineer.mReispsriionntefdrowmithRpeefr.m[2i3ss]i.on from Ref. [23]
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