Redox iron uptake

H. F. Bienfait, Regulated redox proces.ses at the plasmalemma of plant root cells and their function in iron uptake. J. Bioenerg. Biomemhr. 17 13 (1985). 

As mentioned previously, siderophores must selectively bind iron tightly in order to solubilize the metal ion and prevent hydrolysis, as well as effectively compete with other chelators in the system. The following discussion will address in more detail the effect of siderophore structure on the thermodynamics of iron binding, as well as different methods for measuring and comparing iron-siderophore complex stability. The redox potentials of the ferri-siderophore complexes will also be addressed, as ferri-siderophore reduction may be important in the iron uptake process in biological systems. 

Harrington, JM, Crumbliss AL (2009) The Redox Hypothesis in the Siderophore-mediated Iron Uptake. Biometals 22 679... 

Mammalian cells take up iron by three kinds of iron (Fe) uptake systems the transferrin receptor (TfR)-mediated endocytosis, redox, and Tf-independent iron uptake (Tf-IU) systems [1-7] (Fig. 1). 

Oshiro S, Nakajima H, Markello T, Krasnewich D, Bernardini I, Gahl WA (1993) Redox, transferrin-independent, and receptor-mediated endocytosis iron uptake system in cultured human fibroblasts. J Biol Chem 268 21586-21591... 

Fig. 14. Redox cycling in the uptake of copper and iron. The lower valent state species is substrate for uptake of copper and iron. The system in the yeast Saccharomyces cerevisiae is diagrammed. The Frel protein reduces environmental Cu " and Fe +. The cuprous ion is substrate for the copper permease, Ctrip. Fe + is substrate for Fet3p its oxidation to Fe + is an obligate step in iron uptake through Ftrlp. Exogenous ferric iron is not taken up by yeast cells unless it is cycled through the ferrireduction-ferrox-idation reactions catalyzed by Frelp and FetSp.

Rapid iron uptake or release by ferritins to form, or breakdown, a Fe(III) core involves redox reactions, as discussed in previous sections. The present section summarizes data regarding measurement of redox properties not involving iron release or uptake. 

There is still great uncertainty surrounding the formation and breakdown of the iron core of ferritin. For relatively rapid iron uptake and release the iron needs to be in the ferrous state. Thus, because the iron in the core is mostly in the ferric state, most attention has been directed toward redox-linked iron uptake and release. However, Fe + is stable in the core for considerable periods of time 115,144), >16 hr in some studies (116), leading to the suggestion that in vivo not all the iron in the core is Fe ". ... 

In contrast to ferritin, very little work has been done on the reconstitution of BFR cores, other than the experiments mentioned above that showed that, in the absence of phosphate, crystalline ferrihydrite formed inside the protein shell. The intermediate stages in this process are unknown, but the sigmoid iron uptake behavior (25) suggests there could be a similar succession of events oxidation and nucleation on the protein shell followed by direct oxidation on the core. The influence of the heme, if any, on BFR iron core formation also awaits investigation. As mentioned above, the presence of the iron core influences the heme redox potential, but it is not known whether the presence of heme influences the redox potential of the nonheme iron. 

Bienfait, H. F. (1985), Regulated Redox Processes at the Plasmalemma of Plant Root Cells and Their Function in Iron Uptake, J. Bioenerg. Biomem. 17, 73-83. 

If both MT-1 and HO-1 mRNA induction by heme-hemopexin involves a copper-redox enzyme in both heme transport (and consequent induction of HO-1 mRNA) and the signaling pathway for MT-1 expression, a plausible working model can be formulated by analogy with aspects of the yeast iron uptake processes and with redox reactions in transport (Figure 5-6). First, the ferric heme-iron bound to hemopexin can act as an electron acceptor, and reduction is proposed to be required for heme release. The ferrous heme and oxygen are substrates for an oxidase, possibly NADH-dependent, in the system for heme transport. Like ferrous iron, ferrous heme is more water soluble than ferric heme and thus more suitable as a transport intermediate between the heme-binding site on hemopexin and the next protein in the overall uptake process. The hemopexin system would also include a copper-redox protein in which the copper electrons would be available to produce Cu(I), either as the copper oxidase or for Cu(I) transport across the plasma membrane to cytosolic copper carrier proteins for incorporation into copper-requiring proteins [145]. The copper requirement for iron transport in yeast is detectable only under low levels of extracellular copper as occur in the serum-free experimental conditions often used. 

However, the postulated mechanism provides a simple explanation for the effect of anoxemia on iron uptake. The conversion of apoferritin to ferrritin is coupled with the reduction of ferric to ferrous iron. The rate of ferritin formation would be regulated by the redox levels of the cell. Whether this theory for the control of iron uptake will survive a concentrated tide of quantitatively well-controlled in vivo experiments remains to be seen. 

It is clear that ferric chelates present in soil water are the natural electron acceptors for the inducible system (or turbo reductase) responsible for ferric reduction prior to iron uptake by dicotyledoneous and nongrass monocotyledoneous plants (Holden et al., 1991 Lesuisse and Labbe, 1992). In contrast, the natural electron acceptor of the so-called constitutive plasma membrane redox system both in plant and animal cells has not been completely defined. In addition to oxygen and iron-containing compounds, the semioxidized form of ascorbate, AFR, has been proposed as a natural electron acceptor (Goldenberg et al, 1983). 

In addition to the well-characterized role of iron in catalysing redox interactions, other metallic contaminants, for example, nickel, may also contribute. In vivo toxicity studies have demonstrated the capacity of nickel particulate compounds to induce tumours following intraperitoneal injection (Pott etal., 1987). Such activity is proportional to their phagocytic uptake, and to the associated respiratory burst and generation of PMN-derived reactive oxygen metabolites (ROMs), a proposed pathogenic mechanism (Evans et al., 1992a). 

Both iron (II) and iron (III) form complexes with mercaptoacetic acid, SRSH2 (5, 11). The ferrous complexes, Fe(II) (RS)2-2 and Fe(II) (OH) (RS) , are highly air-sensitive and are rapidly oxidized to the intense red ferric complex, Fe(III)OH(RS)2 2 (5). Under air-free conditions the color of this latter complex is observed to fade at moderate to fast rates because of a redox reaction in which the iron is reduced to the ferrous state and the mercaptoacetate is oxidized to the disulfide. Michaelis and Schubert (9) proposed that the catalysis takes place through the alternate oxidation and reduction of iron ions in a sequence similar to that just described, but Lamfrom and Nielsen (4) were able to show that under mildly acid conditions the rate of oxygen uptake of solutions containing iron and... 

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