Copper transport role

In addition to its previously mentioned role in copper transport, ceruloplasmin is an amine oxidase, a superoxide dismutase, and a ferrooxidase able to catalyze the oxidation of Fe2+ to Fe3+. Ceruloplasmin contains three consecutive homologous 350-residue sequences which may have originated from an ancestral copper oxidase gene. Like ascorbate oxidase, this blue protein contains copper of the three different types. Blood clotting factors V and VIII (Fig. 12-17), and the iron uptake protein Fet3 (Section A,l) are also closely related. 

This blue oxidase, present in the plasma of vertebrates, appears to be multifunctional.905,975 It accounts for some 95% of the circulating copper in a normal mammal, and its concentration fluctuates considerably in diseased states. It appears that ceruloplasmin has a major role in copper transport (as discussed in Section 62.1.11). In addition it has oxidase activity towards three groups of substrates, although its physiological role is not known with certainty. 

Early life forms thriving near thermal vents in waters enriched in heavy metal ions would have had to have been endowed with mechanisms to deal with toxic metal ions and it is conceivable that efflux mechanisms for these metals evolved before or concomitandy with their use as cofactors. In line with such a hypothesis, the CPx-type ATPases encompass a wider spectrum of ion specificities than the non-heavy metal ATPases, now including Cu+, Ag+, Zn +, Cd +, and Pb. It is to be expected that other metal ions will be added to this list. ATPases transporting silver, zinc, cadmium, and lead are involved in bacterial resistance to these toxic metal ions, while copper-transporting ATPases have a role both in copper uptake to meet cellular demands and in copper extrusion when ambient... 

Fig. 1. Schematic overview of copper trafficking and homeostasis inside the yeast cell. The actions of Mad and Ace 1, copper-dependent metalloregulatory transcription factors, control the production of copper import [copper transporter (Ctr) and reductase (Fre)] and detoxification/sequestration [metallothionein (MT)] machineries, respectively. Three chaperone-mediated delivery pathways are shown. Atxl shuttles Cu(I) to the secretory pathway P-type ATPase Ccc2 (right). CCS delivers Cu(I) to the cytoplasmic enzyme copper-zinc superoxide dismutase (SOD) (left). Coxl7 shuttles Cu(I) to cytochrome c oxidase (CCO) in the mitochondria (bottom). Mitochondrial proteins Scol and Sco2 may also play a role in copper delivery to the CuA and CuB sites of CCO. Copper metabolism and iron metabolism are linked through the actions of Fet3, a copper-containing ferroxidase required to bring iron into the cell (lower right) (see text).

Dancis, A., Yuan, D. S., Haile, D., Askwith, C., Eide, D., Moehle, C., Kaplan, /., and Klausner, R. D. (1994). Molecular characterization of a copper transport protein in S. cerevisiae An unexpected role for copper in iron transport. Cell 76, 393-402. 

Figure 1 Copper transport pathway. Copper is absorbed in the intestine and becomes bound to amino acids, mainly histidine and albumin. Prior to uptake, Cu(II) is reduced to Cu(I) by a membrane-bound reductase and enters the cell via a passive transporter. Once in the cell, copper becomes bound to copper chaperones responsible for delivering copper to specific proteins. The Wilson/Menkes ATPase accepts copper from these chaperones and pumps it into the Golgi for incorporation into various proteins such as ceruloplasmin (Cp). Ceruloplasmin may also play a role in delivering copper to peripheral tissues via cell-surface receptors that internalize the protein. The Wilson disease ATPase may also play a role in the elimination of copper into the bile...

Safaei R, Holzer AK, Katano K, Samimi G, Howell SB. The role of copper transporters in the development of resistance to Pt drugs. J. Inorgan. Biochem. 2004 98 1607-1613. 

Kuo MT, Chen HH, Song IS, Savaraj N, and IshikawaT.The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26 71-83,2007. 

Lee, J., Prohaska, J. R., Thiele, D. J. (2001). Essential role for mammalian copper transporter Ctrl in copper homeostasis and embryonic development. Proceedings of the National Academy of Sciences of the United States of America, 98, 6842—6847. 

For a long time erythrocuprein was thought to act exclusively as a copper-transporting protein. This was a very attractive conclusion since over 50% of the erythrocyte copper content is present in erythrocuprein (60). However, in the absence of any known function of a metalloprotein, it is always tempting to assign to it the role of storage or transport of the respective metal ions. For example, caeruloplasmin was considered to be the main copper-transporting protein in blood plasma. It subsequently turned out that this copper protein is a key enzyme in iron metabolism, responsible for the oxidation of Fe2+ to the Fe3+ bound in transferrin (130—132). 

Suzuki M and Gitlin JD (1999) Intracdlular localization of the Menkes and Wilson s disease proteins and their role in intracellular copper transport. Pediatr Int 41 436-442. 

Total copper and cadmium concentrations increased from Sites 1-4, ranging from 1.2 to 6.8 /xg/L for copper, and 0.2 to 1.0 /xg/L for cadmium. Copper transported in the dissolved phase ranged from 56% at Site 4 to 68% at Sites 1 and 3, and 80% at Site 2. Dissolved cadmium accounted for more than 50% of the total concentrations at all sites. Thus, copper and cadmium transport in the Mississippi River was dominated by apparent solution-phase transport. Total mean lead concentrations ranged from 2.3 to 5.7 /xg/L at Sites 1-4, with dissolved metal accounting for 16 to 38% of the total. The unexpectedly large contribution of dissolved lead indicates the potential role played by organic matter in maintaining lead in solution. 

Ceruloplasmin (Cp), secreted into the blood stream, appears to be ubiquitous in vertebrates. There is extensive in vitro evidence that Cp efficiently catalyzes the oxidation of Fe to Fe under near physiological conditions. The role of Cp in iron metabolism is widely accepted and there is strong evidence for a secondary role in copper transport/regulation. Defects in hepatic biosynthesis of Cp may result in diseases such as Wilson s disease. There is conclusive evidence that Cp is the source for the copper found in cytochrome c oxidase and CuZn-SOD in cells. Cp inhibition of Fenton chemistry-induced oxidative damage of deoxyribose, lipids, and DNA points to an antioxidant role, which would explain the increase in Cp concentration in response to acute infection or inflammation. 

Apart from its catalytical function, Cu Zn superoxide dismutases was suggested to play a role as copper-transport and/or storage protein Copper depleted E Znj-superoxide dismutase (E = Empty) can be reconstituted using Cu(I)-thiolate proteins (metallothioneins)... 

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