Multicopper oxidases ferroxidases

One of the significant differences between the multicopper oxidases as a group and the ferroxidases is that only the latter efficiently catalyze the... 

Osaki, 1974 Osaki, 1966 Osaki et al., 1966). Using the kinetic values given above, they estimated that without the ferroxidase activity of Cp in the plasma 80% of the iron released from erythrocyte turnover would accumulate as non-Tf-bound Fe(ll) and thereby would be unavailable for reabsorption by the reticuloendothelial system. Furthermore, this free Fe(II) could catalyze the formation of reactive oxygen species via the Fenton reaction. This, in turn, could lead to a subsequent organismal pathophysiology (Miyajima et al., 1996 Nakano, 1993). This inference has been strikingly confirmed by research over the past 6 years in both yeasts and mammals this research has directly tested the hypothesis that multicopper oxidase-dependent ferroxidase activity is essential to eukaryotic iron homeostasis (Askwith et al., 1996 Harris et al., 1995 1998 Wessling-Resnick, 1999). 

Based on present sequence data, known or likely ferroxidase enzymes can be identihed in several eukaryotes. These enzymes are listed in Table 11. All are multicopper oxidases, by sequence homology at least. In mammals, they include ceruloplasmin and, most likely, hephaestin (Hp), although only mouse Hp (mHp) has been characterized at this time (Vulpe et al., 1999). The alignments in Fig. 5A show that mHp is essentially... 

In the yeast Sa. cerevisiae the functional homologue of ceruloplasmin is Fet3. It is a multicopper oxidase that displays ferroxidase activity similar... 

The high-affinity pathway involves oxidation of Fe to Fe by the ferroxidase FET3 and subsequent transport of Fe " " across the plasma membrane by the permease FTRl. FET3p is a member of the family of multicopper oxidases, which include ascorbate oxidase, laccase, and ceruloplasmin (see Chapter 14), and does not become functional until it is loaded with copper intracellularly through the activities of the copper chaperone ATX Ip and the copper transporter CCC2p. It appears that Fe " " produced by FET3 is transferred directly to FTRl, and does not equilibrate with the bulk phase, as is illustrated in Fig. 7.13. This is almost certainly achieved by the classic metabolite-channeling mechanism, a common feature of multifunctional enzymes. 

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. ... 

Multicopper Oxidases (Blue Copper Oxidases) Ascorbate Oxidase, Ceruloplasmin, and Laccase. The multicopper oxidases (MCOs) are important enzymes, which are found in many plants (lignin formation), fungi (lignin degradation and detoxification), bacteria, as well as humans (ferroxidase activity) (13). MCOs catalyze the four-electron reduction of O2 to two waters with the electrons coming firom one-electron oxidation of four substrate molecules. The latter are organic reductants for ascorbate oxidase (AO) (32) and laccase (Lc) (130), and a metal ion (ferrous ion) for ceruloplasmin (Cp) (33) (Scheme 9). 

The anemia is characterized as hypochromic and normocytic with a reduced reticulocyte count, hypo-ferremia, and thrombocytopenia. Bone marrow aspirate reveals megaloblastic changes and vacuolization of both erythroid and myeloid progenitor lineages. It is believed that a profound copper deficiency results in a multicopper oxidase deficient state and as such bone marrow demands are unmet by the lack of ferroxidase activity. Bone abnormalities are common and manifest as osteoporosis, fractures, and epiphyseal separation. Other manifestations of copper deficiency include hypopigmentation, hypotonia, growth arrest, abnormal cholesterol and glucose metabolism, and increased rate of infections. 

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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