Plasma ferroxidase activity

If iron mobilization is dependent on Cp, shouldn t there be a disturbance in iron metabolism, perhaps resembling copper deficiency, in Wilson s disease This is a disorder characterized by low plasma Cp and the accumulation of copper in the liver and brain. It is treated by eliminating copper from the diet and/or removing copper by administering penicillamine. However, the evidence to support a concomitant upset in iron utilization is tenuous. There is one recent paper by O Reilly et al. (51) in which eight patients with Wilson s disease were reported to have iron deficiency or low plasma iron or both, sometimes associated with anemia. Most of these subjects had low or low-normal levels of transferrin. One mitigating factor is that the size of the spleen in Wilson s disease is almost doubled and this may permit a more rapid turnover of plasma iron despite the low plasma ferroxidase activity. 

Another condition involving ceruloplasmin is aceru-loplasminemia. in this genetic disorder, levels of ceruloplasmin are very low and consequently its ferroxidase activity is markedly deficient. This leads to failure of release of iron from cells, and iron accumulates in certain brain cells, hepatocytes, and pancreatic islet cells. Affected individuals show severe neurologic signs and have diabetes mellitus. Use of a chelating agent or administration of plasma or ceruloplasmin concentrate may be beneficial. 

Cartwright and Wintrobe and their co-workers suggested a link between copper deficiency and anemia in mammals 50 years ago (see Lahey et al., 1952). Cartwright subsequently demonstrated that this copper-dependent anemia was unresponsive to iron supplementation but was corrected on administration of ceruloplasmin (see Lee et al., 1968). The molecular basis of this link was indicated by Osaki and Friedan, who characterized the ferroxidase activity of ceruloplasmin and kinetically demonstrated that Cp could play a critical role in catalyzing trafficking of the potentially cytotoxic Fe(II) in the plasma to apoA f (see Frieden and... 

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). 

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. ... 

The evidence that ceruloplasmin (Cp) (E.C. 1.12.3,1) is a direct molecular link between copper and iron metabolism is summarized. Copper deficiency results in low plasma Cp and iron, reduced iron mobilization, and eventually anemia, even with high iron storage in the liver. Cp controls the rate of iron uptake by transferrin. Transferrin plays a key role in the availability of iron for the biosynthesis of hemo-globin in the reticulocytes. The ferroxidase activity of Cp results in the reduction of free iron ion generating a conr centration gradient from the iron stores to the capillary system, thus promoting a rapid iron efflux in the reticuloendothelial system. It has been confirmed both in vivo and in the perfused liver that lOr M Cp specifically induces a rapid rise in plasma iron. 

Ferrireductases and ferroxidases Ceruloplasmin (Cp) Duodenal cytochrome b Hephaestin Steap proteins Plasma protein with ferroxidase activity involving in cellular iron export Membrane ferric reductase involving in cellular iron uptake Membrane Cp homolog functioning in enterocyte iron export Ferrireductases required for iron uptake in Tf cycle... 

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. 

There is evidence of an increase in the redox-active fraction of plasma Cu in human aging [54]. This arises because of the apparent increase in the proportion of an oxidized form of ceruloplasmin, an antioxidant ferroxidase that carries > 90% of total plasma Cu. The damaged ceruloplasmin allows the Cu it binds (6 moles per protein unit) to become EPR-detectable [54]. This is an example of how damage to a cuproprotein may unleash abnormal redox chemistry, a principle that we believe underhes the pathology of AD. 

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