Homeostasis copper

The recent high resolution structure of CueO, an enzyme required for Cu homeostasis in the gut bacterium Escherichia coli has provided the clearest view of the four-copper active site so far [27]. For instance, the TI Cu site that has normally been described as distorted tetrahedral [24] can now be characterized as trigonal bipyramidal with a missing Hgand as in the weU-studied azurins. However, the oxidation states of the Cu ions in the crystal structure have not been characterized. 

Iron is the most common trace metal in most organisms. As heme iron, it is involved in storage and transport of O2 and respiration, it also mediates electron transfer forming FeS clusters and catalyzes a great number of reactions, many of them involving intermediates of the reduction of molecular oxygen to water and 

Binding iron to proteins helps to prevent this reaction. Another way to avoid the generation of the aggressive hydroxyl radical is to lower the concentration of hydrogen peroxide by the action of catalases and peroxidases [38]. Other enzymes such as superoxide dismutases, which neutralize the reactive 02 ion, are also part of the detoxificating machinery of the cell. A few examples of iron enzymes are described below. 

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Adaikkalam V, S Swarup (2002) Molecular characterization of an operon, cueAR, encoding a putative Pl-type ATPase and a MerR-type regulatory protein involved in copper homeostasis in Pseudomonas putida. Microbiology (UK) 148 2857-2867. 

Figure 12.2 Copper chaperone function, (a) Copper homeostasis in Enterococcus hirae is affected by the proteins encoded by the cop operon. CopA, Cu1+-import ATPase CopB, Cu1+-export ATPase CopY, Cu1+-responsive repressor copZ, chaperone for Cu1+ delivery to CopY. (b) The CTR family of proteins transports copper into yeast cells. Atxlp delivers copper to the CPx-type ATPases located in the post Golgi apparatus for the maturation of Fet3p. (c) Coxl7p delivers copper to the mitochondrial intermembrane space for incorporation into cytochrome c oxidase (CCO). (d) hCTR, a human homologue of CTR, mediates copper-ion uptake into human cells. CCS delivers copper to cytoplasmic Cu/Zn superoxide dismutase (SOD1). Abbreviations IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane PM, plasma membrane PGV, post Golgi vessel. Reprinted from Harrison et al., 2000. Copyright (2000), with permission from Elsevier Science.

Figure 4.5 Fet3p and copper homeostasis. Defects in the plasma membrane transporters Ctrl and Ctr3, the cytosolic copper chaperone Atxlp, or the vesicular copper transporter Ccc2p affect Fet3p activity. Reprinted from Askwith and Kaplan, 1998. Copyright (1998), with permission from Elsevier Science.

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in liver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa (USEPA 1980 Aaseth and Norseth 1986). Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive... 

Handy, R. D. and Eddy, F. B. (2004). Transport of solutes across biological membranes in eukaryotes sodium and copper homeostasis in gill epithelial cells, In Physicochemical Kinetics and Transport at Biointerfaces, eds. van Leeuwen, H. P. and Koster, W., Yol. 9, IUPAC Series on Analytical and Physical Chemistry of Environmental Systems, Series eds. Buffle, J. and van Leeuwen, H. P., John Wiley Sons, Ltd, Chichester, pp. 337-356. 

Metallothionein was first discovered in 1957 as a cadmium-binding cysteine-rich protein (481). Since then the metallothionein proteins (MTs) have become a superfamily characterized as low molecular weight (6-7 kDa) and cysteine rich (20 residues) polypeptides. Mammalian MTs can be divided into three subgroups, MT-I, MT-II, and MT-III (482, 483, 491). The biological functions of MTs include the sequestration and dispersal of metal ions, primarily in zinc and copper homeostasis, and regulation of the biosynthesis and activity of zinc metalloproteins. 

Solioz, M. and Stoyanov, J.V. (2003) Copper homeostasis in Enterococcus hirae, FEMS Microbiol. Rev., 27, 183-195. 

Figure 8.5 Model of copper homeostasis in E. hirae. (From Magnani and Solioz, 2005. With kind permission of Springer Science and Business Media.)...

Figure 8.10 Model of copper homeostasis in S. cerevisiae. (From Cobine et al., 2006. Copyright 2006, with permission from Elsevier.)...

In a manner similar to copper homeostasis, zinc homeostasis in mammals involves post-translational mechanisms. Both Zipl and Zip3 are found predominantly at the plasma... 

Bertinato, J. and L Abbe, M.R. (2004) Maintaining copper homeostasis regulation of copper-trafficking proteins in response to copper deficiency or overload, J. Nutr. Biochem., 15, 316-322. 

Rutherford, J.C. and Bird, A.J. (2004) Metal-responsive transcription factors that regulate iron, zinc, and copper homeostasis in eukaryotic cells, Eukaryot. Cell, 3, 1-13. 

Evidence is also growing that PsPc plays an important role in copper homeostasis, in particular at the pre-synaptic membrane that it may be involved in triggering intracellular calcium signals and that it may play a neuroprotective role in response to copper and oxidative stress (Figure 18.6). Exposure of neuroblastoma cells to high Cu(II) concentrations stimulated endocytosis of PsPc, whereas deletion of the four octarepeats or mutation of the histidine residues in the central two repeats abolished endocytosis of PsPc (see Chapter 8). 

Figure 18.6 Schematic representation of the physiological role of prion protein (Prpc) in copper homeostasis and redox signalling. (From Crichton and Ward, 2006. Reproduced with permission from John Wiley Sons., Inc.)...

Copper thionein Copper homeostasis Vertebrates Weser and Hartmann (1984)... 

Copper is essential for some of the enzymes that have a role in brain metabolism. Sophisticated mechanisms balance copper import and export to ensure proper nutrient levels (homeostasis) while minimizing toxic effects. Several neurodegenerative diseases including AD are characterized by modified copper homeostasis. This change seems to contribute either directly or indirectly to increased oxidative stress, an important factor in neuronal toxicity. The association of misfolded proteins and modified copper homeostasis appears to be important in the pathological progression of AD [Donnelly et al., 2007],... 

The copper-binding APP and Ap have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced copper homeostasis with a causative or diagnostic link to AD. Whereas elevated copper levels are observed in APP knockout mice, APP overexpression results in reduced copper in transgenic mouse brain. Moreover, copper induces a decrease in Ap levels in APP-transfected cells in vitro. To investigate the... 

Wilson s disease is a pathological accumulation of copper in tissue which is later released into the bloodstream, leading to anaemia, and final accumulation of copper in liver and brain. It is the result of a mutation in the Wilson s disease gene in chromosome 13 which ordinarily codes for a cation transporting ATPase so that copper can be incorporated into ceruloplasmin prior to excretion. Also known as ferroxi-dase, in acknowledgement of its primary function as an oxidoreductase responsible for electron transfer, this enzyme contains iron and, more importantly, six copper atoms. It accounts for the transport of 90% of copper in the plasma so any impairment in its production or efficacy has a major impact on copper homeostasis. The greatly reduced concentration of ceruloplasmin in the blood of Wilson s disease sufferers correlates with their inability to metabolize copper effectively. It leads to chronic liver disease, for which the only real cure is a liver transplant,... 

Several papers utilizing 3 mm probe capabilities were also published that delved into the area of protein structures. Hepatocyte nuclear factor 4 was studied by a group lead by Williams.155 It is interesting to note that a 2.7 A X-ray study showed a fatty acid in the pocket of HNF4y. Gas chromatography coupled mass spectrometry (GC/MS) and 3 mm NMR studies of extracts from purified HNF4x led to the identification of mixtures of saturated and crs-monounsaturated Ci4 to Qg fatty acids. Bertini and co-workers156 utilized 3 mm probe capabilities in the determination of the solution structure of CopC, a cupredoxin-like protein involved in copper homeostasis. 

All cells appear to have a complex thermostat-hke control system for sensing copper status. Various setpoints must exist in the thermostat system to achieve copper homeostasis. Distinct Cu sensory/transduction systems respond to the various setpoints. Future research will be needed to establish the signal sensed and what determines the setpoint of the cellular copper thermostat. 

Fig. 5. Copper homeostasis in Enterococcus hirae. Under copper-limiting conditions, copper is pumped into the cell by CopA. The CopZ copper chaperone picks up copper at this site of entry. Under physiological copper conditions, Zn(II)CopY binds to the promoter and represses transcription of the cop operon. Under conditions of copper excess, Cu-CopZ donates Cu(I) to CopY, which leads to the replacement of the Zn(II), loss of DNA-binding affinity, and ultimately synthesis of the operon products. Excess copper is secreted by the CopB efflux pump. The substrate for this pump may be a copper-glutathione (GSH) complex, rather than Cu-CopZ.

Today, copper homeostasis is a research area of intense interest and work in this field has recently uncovered several surprising new concepts of trace metal homeostasis, and more are likely to emerge. The molecular defects in the inherited disorders of copper metabohsm, Menkes disease... 

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