Iron transport Multicopper oxidases

Buonaccorsi di Patti, M. C., Pascarella, S., Gatalucci, D., and Galabrese, L. (1999). Homology modeling of the multicopper oxidase Fet3 gives new insights in the mechanism of iron transport in yeast. Protein Eng. 12, 895-897. 

Spizzo, T, Byersdorfer, C., Duesterhoeft, S., and Eide, D. (1997). The yeast FET5 gene encodes a FET3-related multicopper oxidase implicated in iron transport. Mol. Gen. Genet. 256, 547-556. 

In the area of copper metabolism, four topics are covered bacterial copper transport reviewed by Huat Lu and Sohoz copper P-type ATPases reviewed by Voskoboinik, Camakaris, and Mercer copper chaperones reviewed by Stine Elam et al. and copper metaUoregulation of gene expression reviewed by Winge. An important related topic is the link between copper and iron metabolism. In this area, Kosman has reviewed the multicopper oxidase enzymes, such as FetSp and ceruloplasmin, which catalyze the conversion of iron(II) to iron(III) in preparation for its specific transport by partner transporter proteins. 

FET3 gene product of S. cerevisiae is a multicopper oxidase and plays a key role in iron metabolism of this eukaryote has underpinned the function of ceruloplasmin in vertebrate iron transport. By virtue of its ferroxidase activity, ceruloplasmin converts Fe(II) into Fe(III), which binds to the iron-binding protein transferrin. Ceruloplasmin is critical for iron egress from some cell types. The transport system responsible for iron release into plasma has not been identified. ... 

Similar to the occurence in animals, iron deprivation in the yeast Saccharomyces cerevisiae induces the expression of a high affinity iron transport system, and the mechanism by which the signal is transduced is partially understood. Ferric iron is reduced to Fe via Frel/Fre2, and subsequently reoxidized and transported into cells by Fet3 and Ftrl, respectively (reviewed in [49], see Chapter 4 and [50]). Fet3 is a multicopper oxidase homologous to ceruloplasmin it requires the protein Ccc2 for... 

The accumulation of iron is dependent on its transport into the cell. Askwith and Kaplan (Chapter 4) discuss iron transport mechanisms in eukaryotic cells, developing models based on studies carried out in the yeast, Saccharomyces cerevisiae. These cells possess both siderophore-dependent and elemental iron transport systems. The latter system relies on cell surface ferrireductases to convert extracellular ferric chelates to ferrous iron, which can be transported through either a high or low affinity iron transport system. Studies on a high affinity ferrous iron transporter (FET3) revealed that the multicopper oxidase will oxidize ferrous to ferric iron, which is then mobilized across the membrane by a ferric transmembrane permease (Ftrlp). This is a highly specific transport system in yeast it only transports iron. In humans, the copper enzyme, ceruloplasmin, is responsible for the radical-free oxidase activity. This plasma protein oxidizes the ferrous iron that is excreted from cells into the transferrin-usable ferric form. 

Once inside the mucosal cell, iron then has to be transported across the membrane to serum transferrin. This appears to take place via the Iregl transporter protein (also known as ferroportin 1 or MTPl). Iregl is a transmembrane protein located at the basolateral membrane of the cell that has been shown to be involved in iron uptake. Oxidation of Iregl-bound ferrous iron and its release to transferrin is likely to be enhanced by the membrane-bound multicopper ferroxidase hephaestin. This protein is 50% identical to ceruloplasmin, a soluble protein identified as having a possible role in iron loading of transferrin see Copper Proteins Oxidases). Mutation of hephaestin in mice leads to a build up of iron in duodenal cells and overall iron deficiency in the body. ... 

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