Abstract
Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans—ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe2+, but transferrin, the major iron transporter protein of blood, can bind only Fe3+ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis.
Highlights
Recent studies of SLC11A2 knockout mice have shown that DMT1 plays a significant role in intestinal iron absorption and iron uptake by erythroid cells, but the transporter is dispensable in placenta and liver [15]
Transferrin endocytosis is mostly mediated by transferrin receptor 1 (TfR1), a ubiquitously expressed membrane protein that binds holotransferrin with an affinity of 109/M [39]
By acting on ferroportin, hepcidin controls the three main entries of iron into plasma: (1) from duodenal enterocytes absorbing dietary iron, (2) from macrophages involved in the recycling of iron from erythrocytes, and (3) from hepatocytes involved in iron storage
Summary
Iron is an essential element in most biological systems. Only members of the Lactobacillus and Bacillus families can sustain life without iron [1]. As a part of a binuclear site in ribonucleotide reductase, iron serves as an important factor in the synthesis of DNA [5] In addition to these functions as a protein cofactor, iron has been implicated as playing a role in the immune response [6]. At neutral pH and physiological oxygen tension, Fe(II) is readily oxidized into Fe(III) Under these conditions, Fe(III) tends to hydrolyze and forms the extremely insoluble Fe(OH) complex. Since both iron overload and iron deficiency cause cell death, the levels of biologically available iron must be tightly controlled. This set of conditions has led to the development of elaborate mechanisms of iron acquisition, trafficking and storage
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