Redox Cycling in Iron Uptake, Efflux, and Trafficking

Abstract

Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).Following the first crystallization of a protein, jack bean urease, reported by Sumner in 1926 (1), the evolution of protein chemistry remained a slow process, hampered by limitations in techniques for protein resolution and analysis. Not surprisingly, many proteins obtained in relatively pure form were those with prosthetic metal ion groups that imparted a visible absorbance to guide the purification. Some were copper proteins whose Cu(II) spectral properties gave their protein host a greenish blue to bright blue hue. Two of these were from mammalian whole blood: hemocuprein (cupric species from erythrocytes, superoxide dismutase) and ceruloplasmin (cerulean blue species from plasma). Superoxide dismutase was first isolated in 1938 by Mann and Keilin (5); Cp 2 was first isolated in 1948 by Holmberg and Laurell (6). Both proteins play essential roles in aerobic homeostasis. In the case of ceruloplasmin and the other copper proteins that share its substrate specificity, this role is to manage the redox state of iron in the metabolism of this essential yet potentially cytotoxic transition metal ion. These proteins, all of which are members of the MCO family (7-9), and the mechanism by which they provide this function are a focus of this minireview.

Systems and Trans-System Level Analysis Identifies Conserved Iron Deficiency Responses in the Plant Lineage

“…Accordingly, iron metabolism uses transport systems involving chelation and redox chemistry (often multiple sequential steps) followed by biosynthesis of heme, inorganic Fe/S, or other clusters (Theil, 2004;Lill and Mühlenhoff, 2008;Philpott and Protchenko, 2008;Kosman, 2010). In eukaryotic cells, there is the additional complication of subcellular compartmentation and delivery of iron or assembled cofactors across membranes, and this is exacerbated in plants where the plastid is yet another compartment (Jeong and Guerinot, 2009).…”

Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster

“…Redox cycling between the two oxidation states is a critical aspect of iron metabolism because the two forms of iron have different properties: ferrous iron is soluble under most physiological conditions, but it participates in toxic radical formation, whereas ferric iron does not promote radical formation, but it is highly insoluble (1). Multicopper ferroxidases in yeast and algae function in the uptake of iron by oxidizing ferrous to ferric iron, which is then transported into the cell by a ferric iron permease (2,3).…”

“…This article is a PNAS Direct Submission. 1 To whom correspondence should be addressed. E-mail: mgorman@ksu.edu.…”

Inorganic Signatures of Physiology: The X-Ray Fluorescence Microscopy Revolution

“…Good recent reviews of biological copper (Boal and Rosenzweig 2009;Banci, Bertini et al 2010;Lutsenko 2010), iron (Kosman 2010), and zinc (Eide 2006;Tomat and Lippard 2010) exist. Our understanding of the location and bioavailability of metals, until rather recently, was mainly accessible by studying the properties of the proteins that bind them.…”