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      Multi-Copper Oxidases and Human Iron Metabolism

      review-article
      1 , 2 , *
      Nutrients
      MDPI
      multi-copper oxidase, ferroxidase, ceruloplasmin, hephaestin, zyklopen

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          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 Fe 2+, but transferrin, the major iron transporter protein of blood, can bind only Fe 3+ 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.

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          Laccases: a never-ending story.

          Laccases (benzenediol:oxygen oxidoreductases, EC 1.10.3.2) are blue multicopper oxidases that catalyze the oxidation of an array of aromatic substrates concomitantly with the reduction of molecular oxygen to water. In fungi, laccases carry out a variety of physiological roles during their life cycle. These enzymes are being increasingly evaluated for a variety of biotechnological applications due to their broad substrate range. In this review, the most recent studies on laccase structural features and catalytic mechanisms along with analyses of their expression are reported and examined with the aim of contributing to the discussion on their structure-function relationships. Attention has also been paid to the properties of enzymes endowed with unique characteristics and to fungal laccase multigene families and their organization.
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            A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.

            Iron absorption by the duodenal mucosa is initiated by uptake of ferrous Fe(II) iron across the brush border membrane and culminates in transfer of the metal across the basolateral membrane to the portal vein circulation by an unknown mechanism. We describe here the isolation and characterization of a novel cDNA (Ireg1) encoding a duodenal protein that is localized to the basolateral membrane of polarized epithelial cells. Ireg1 mRNA and protein expression are increased under conditions of increased iron absorption, and the 5' UTR of the Ireg1 mRNA contains a functional iron-responsive element (IRE). IREG1 stimulates iron efflux following expression in Xenopus oocytes. We conclude that IREG1 represents the long-sought duodenal iron export protein and is upregulated in the iron overload disease, hereditary hemochromatosis.
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              A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake.

              The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis due to interleukin-3 (IL-3) deprivation and iron transport. Here we report cloning of the 24p3 cell-surface receptor (24p3R). Ectopic 24p3R expression confers on cells the ability to undergo either iron uptake or apoptosis, dependent upon the iron content of the ligand: Iron-loaded 24p3 increases intracellular iron concentration without promoting apoptosis; iron-lacking 24p3 decreases intracellular iron levels, which induces expression of the proapoptotic protein Bim, resulting in apoptosis. Intracellular iron delivery blocks Bim induction and suppresses apoptosis due to 24p3 addition or IL-3 deprivation. We find, unexpectedly, that the BCR-ABL oncoprotein activates expression of 24p3 and represses 24p3R expression, rendering BCR-ABL(+) cells refractory to secreted 24p3. By inhibiting BCR-ABL, imatinib induces 24p3R expression and, consequently, apoptosis. Our results reveal an unanticipated role for intracellular iron regulation in an apoptotic pathway relevant to BCR-ABL-induced myeloproliferative disease and its treatment.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                27 June 2013
                July 2013
                : 5
                : 7
                : 2289-2313
                Affiliations
                [1 ]Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T1Z3, Canada; E-Mail: ganna.vashchenko@ 123456gmail.com
                [2 ]Department of Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T1Z3, Canada
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: macg@ 123456mail.ubc.ca ; Tel.: +1-604-822-3027; Fax: +1-604-822-7742.
                Article
                nutrients-05-02289
                10.3390/nu5072289
                3738974
                23807651
                65161c55-39c0-490e-a804-3f990a836b77
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 11 March 2013
                : 29 May 2013
                : 06 June 2013
                Categories
                Review

                Nutrition & Dietetics
                multi-copper oxidase,ferroxidase,ceruloplasmin,hephaestin,zyklopen
                Nutrition & Dietetics
                multi-copper oxidase, ferroxidase, ceruloplasmin, hephaestin, zyklopen

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