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PubMed1991

Increase of Cu,Zn-superoxide dismutase activity during differentiation of human K562 cells involves activation by copper of a constantly expressed copper-deficient protein.

Cu,Zn-superoxide dismutase activity, expressed on the basis of cell number, increased by 50% during sodium butyrate-induced differentiation of human K562 erythroleukemia cells. The increased enzyme activity was found to be concomitant with constant Cu,Zn-superoxide dismutase mRNA and immunoreactive protein levels and was accompanied by a rise in intracellular copper and glutathione. Incubation of K562 cell homogenates with copper caused an increase of Cu,Zn-superoxide dismutase activity which reached the levels observed after differentiation in the presence of sodium butyrate. The same treatment led to no significant activity increase in homogenates derived from differentiated cells. Externally added ceruloplasmin increased both intracellular copper levels and Cu,Zn-superoxide dismutase activity in undifferentiated cells to a level comparable with that observed after induction of differentiation. Both increments were abolished by depletion of cell glutathione. Cu,Zn-superoxide dismutase purified from control cells had both a lower kcat and a lower copper content than the enzyme purified from differentiated cells. From these data we conclude that: 1) Cu,Zn-superoxide dismutase is present in K562 cells also under the form of a less active copper-deficient enzyme, 2) the extent of enzyme activation is regulated post-translationally by differential delivery of copper as a function of differentiation stage, and 3) glutathione is likely to play a role in delivering copper to the copper-deficient protein in intact K562 cells.

Catalase↗

PubMed1985

The effect of cow's dietary copper intake, sire breed, age on her copper status and that of her fetus in the first ninety days of gestation.

The liver copper concentration of the bovine fetus and the hepatic and plasma copper concentrations of its dam during the first trimester of pregnancy were studied. The effect of the dam's dietary copper intake, age, sire breed and stage of pregnancy on her copper status and that of her fetus was also investigated. Simmental sired heifers had the lowest plasma copper concentration. The younger cows (two, three and four years) had significantly lower liver copper concentration than the older cows (six and seven years). The bovine fetal liver copper concentration was approximately 3.1 mmol/g DM and was not affected by dam's age, breed, stage of pregnancy, or copper status.

Animal Feed↗

PubMed1979

X-irradiation effects on lipid peroxidation and superoxide dismutase and catalase activities in copper deficient and copper loaded rat liver.

The whole body X-irradiation was found to intensify the lipoperoxidative processes in rat liver mitochondria and microsomes, which resulted in a two-fold increase of hydroperoxides in the membrane lipids. The moderate copper-loading of the liver cell had a protective effect against X-ray induced lipid peroxidation. The X-ray influence on the superoxide dismutase (SOD) and catalase activity in normocupric state, copper deficiency and copper loading was also studied. The latter two states were used as models of altered enzyme activity. Copper deficiency decreased the specific SOD activity in both mitochondrial fraction and cytosol, while the increased copper cell content activated this enzyme in mitochondria and did not change it in cytosol. Irradiation inhibited SOD in all preparations studied, with the exception of cytosol upon copper deficiency. Whatever the cell level of copper, X-ray exposure resulted in a decrease of catalase activity in cytosol, while in the mitochondrial fraction, including peroxisomes, the irradiation effects were different. It was found that both SOD and catalase after whole-body irradiation exhibited a higher specific activity in mitochondrial fraction upon copper loading compared with normocupric state, which correlates with the delayed lipid peroxidation processes.

Animals↗

PubMed1994

Impaired hepatic copper homeostasis in Long-Evans Cinnamon rats: reduced biliary excretion of copper.

To explain the pathogenesis of excessive copper accumulation in Long-Evans Cinnamon (LEC) rats, regarded as one of the animal models for hepatic-type Wilson's disease, we measured copper contents in liver tissue and bile, serum total copper concentration, and ceruloplamin oxidase activity in LEC rats before and after the onset of spontaneous hepatitis. The copper contents in liver tissue of both 11-wk-old and 18-mo-old LEC rats were about 60 times the amounts in age-matched Wistar and Long-Evans Agouti rats. The biliary copper excretion in 11-wk-old LEC rats was significantly lower than that of the Long-Evans Agouti and Wistar rats that were the same age (27.9 and 41.4%, respectively). In 18-mo-old LEC rats, biliary copper excretion was lower than that in the Long-Evans Agouti rats that were the same age, but the finding was statistically not significant. Serum copper and ceruloplasmin levels were markedly reduced in LEC rats of both ages. These findings suggest that LEC rats have similar defects of biliary copper excretion as observed in patients with Wilson's disease.

Animals↗

PubMed1989

Inhibition of Chlamydia trachomatis growth in endometrial cells by copper: possible relevance for the use of the copper IUD.

There is agreement that the relative risk of developing pelvic inflammatory disease (PID) increases among women who use the intrauterine contraceptive device (IUD). The role of Chlamydia in causing PID among IUD users is not clear. The present study demonstrates that Chlamydia trachomatis growth can be inhibited in cultured human endometrial cells by copper ions at concentrations known to be released by the copper IUDs. More than 98% inhibition was produced with 10(-5) and 10(-6) M of copper. Both C. trachomatis serovar E and a lymphogranuloma venereum Chlamydia serovar L2 (LGV) were inhibited by the copper ions. Although the mechanism of the inhibition is not known, the continuous presence of the copper ions during and after adherence appeared to be necessary for maximal effect. If such inhibition occurs in vivo, it is possible that copper ions released from the copper-containing IUD may partially protect against chlamydial infection.

Cells, Cultured↗

PubMed2004

Binding of copper(I) by the Wilson disease protein and its copper chaperone.

The Wilson disease protein (WND) is a transport ATPase involved in copper delivery to the secretory pathway. Mutations in WND and its homolog, the Menkes protein, lead to genetic disorders of copper metabolism. The WND and Menkes proteins are distinguished from other P-type ATPases by the presence of six soluble N-terminal metal-binding domains containing a conserved CXXC metal-binding motif. The exact roles of these domains are not well established, but possible functions include exchanging copper with the metallochaperone Atox1 and mediating copper-responsive cellular relocalization. Although all six domains can bind copper, genetic and biochemical studies indicate that the domains are not functionally equivalent. One way the domains could be tuned to perform different functions is by having different affinities for Cu(I). We have used isothermal titration calorimetry to measure the association constant (K(a)) and stoichiometry (n) values of Cu(I) binding to the WND metal-binding domains and to their metallochaperone Atox1. The association constants for both the chaperone and target domains are approximately 10(5) to 10(6) m(-1), suggesting that the handling of copper by Atox1 and copper transfer between Atox1 and WND are under kinetic rather than thermodynamic control. Although some differences in both n and K(a) values are observed for variant proteins containing less than the full complement of six metal-binding domains, the data for domains 1-6 were best fitted with a single site model. Thus, the individual functions of the six WND metal-binding domains are not conferred by different Cu(I) affinities but instead by fold and electrostatic surface properties.

Adenosine Triphosphatases↗

PubMed2003

Redox-adaptable copper hosts. Pyridazine-linked cryptands accommodate copper in a range of redox States.

A series of structurally characterized copper complexes of two pyridazine-spaced cryptands in redox states + (I,I), (II,I), (II), (II,II) are reported. The hexaimine cryptand L(I) [formed by the 2 + 3 condensation of 3,6-diformylpyridazine with tris(2-aminoethyl)amine (tren)] is able to accommodate two non-stereochemically demanding copper(I) ions, resulting in [Cu(I)(2)L(I)](BF(4))(2) 1, or one stereochemically demanding copper(II) ion, resulting in [Cu(II)L(I)()](BF(4))(2) 3. Complex 3 crystallizes in two forms, 3a and 3b, with differing copper(II) ion coordination geometries. Addition of copper(I) to the monometallic complex 3 results in the mixed-valence complex [Cu(I)Cu(II)L(I)](X)(3) (X = PF(6)(-), 2a; X = BF(4)(-), 2b) which is well stabilized within this cryptand as indicated by electrochemical studies (K(com) = 2.1 x 10(11)). The structurally characterized, octaamine cryptand L(A), prepared by sodium borohydride reduction of L(I), is more flexible than L(I) and can accommodate two stereochemically demanding copper(II) ions, generating the dicopper(II) cryptate [Cu(II)(2)L(A)](BF(4))(4) 4. Electrochemical studies indicate that L(A) stabilizes the copper(II) oxidation state more effectively than L(I); no copper redox state lower than II,II has been isolated in the solid state using this ligand.

Journal Article↗

PubMed1990

An assessment of the copper status of dairy herds in the Waikato, Taranaki and Northland in spring and the effects of daily supplementation with copper sulphate.

The copper status of dairy herds in the Waikato, Taranaki and Northland regions between 1 August and 30 September was assessed by copper determinations made on composite sera from ten cows in each herd. Comparisons were made between two major groups categorised as as received and supplemented. In the latter, the cows received 2.0-6.0 g/day of copper sulphate orally from late gestation to the end of lactation. Mean copper values were determined from pastures in Taranaki and Northland and from pastures from three soil types in the Waikato. The lowest were in Northland (134.3 micromol/kg) and the highest in Taranaki (173.3 micromol/kg). Calculated dietary available copper levels showed the lowest were from pastures grown on organic soils in the Waikato. These soils also had high molybdenum levels. Serum copper values as received were lowest in Northland (7.30 micromol/l), and were marginal for both Taranaki (9.91 micromol/l) and the Waikato (9.93 micromol/l). The levels in supplemented herds were considerably higher, i.e. from the Waikato 11.7 micromol/l and from Taranaki 11.5 micromol/l. When liver and serum copper levels from paired samples were compared there was a reasonable correlation (r = 0.64) but the standard deviation approximated the mean liver copper level, i.e. 155 +/- 141 micromol/l.

Journal Article↗

PubMed1980

Identification of the Low Molecular Weight Copper Protein from Copper-intoxicated Mung Bean Plants.

Mung bean plants (Wilczek) accumulate increasingly greater amounts of buffer-extractable copper in both their shoots and roots when grown in liquid medium containing greater than 2 micrograms per milliliter copper (31.4 micromolar) as cupric sulfate. This increase in soluble copper is accompanied by an increase in the relative amount of low molecular weight (7,000 to 20,000) macromolecular-bound copper and a decrease in the relative amount of high molecular weight (greater than 20,000) copper. The major low molecular weight copper protein has been isolated from copper-intoxicated mung bean plants by a combination of ammonium sulfate fractionation, gel filtration, and ion exchange chromatography. It was identified as mung bean plastocyanin on the basis of its molecular weight, optical behavior, and amino acid composition. No evidence was found for a low molecular weight copper-binding protein corresponding to mammalian thionein or chelatin.

Journal Article↗

PubMed2004

A docking approach to the study of copper trafficking proteins; interaction between metallochaperones and soluble domains of copper ATPases.

A structural model of the transient complex between the yeast copper chaperone Atx1 and the first soluble domain of the copper transporting ATPase Ccc2 was obtained with HADDOCK, combining NMR chemical shift mapping information with in silico docking. These two proteins are involved in copper trafficking in yeast cells. Calculations were performed starting with the copper ion either bound to Atx1 or to Ccc2 and using the experimental structures of the copper-loaded and apo forms of each protein. The copper binding motifs of the two proteins are found in close proximity. Copper tends to move from Atx1 to Ccc2, consistent with the physiological direction of transfer, with concomitant structural rearrangements, in agreement with experimental observations. The interaction is mainly of an electrostatic nature with hydrogen bonds stabilizing the complex. The structural data are relevant for a number of proteins homologous to Atx1 and Ccc2 and conserved from bacteria to humans.

Carrier Proteins↗

PubMed2004

Occurrence of copper resistant mutants in the toxic cyanobacteria Microcystis aeruginosa: characterisation and future implications in the use of copper sulphate as algaecide.

Freshwater toxic cyanobacteria are an increasing problem to human and animal health. Control of cyanobacteria in water supply reservoirs involves the use of algaecides, such as copper sulphate, usually in a repetitive way. Repercussions of recurrent algaecide treatments on cyanobacteria population dynamics remain still unknown. We studied the adaptation of cyanobacteria to lethal doses of copper sulphate by using Microcystis aeruginosa as an experimental model. A fluctuation analysis demonstrated that copper-resistant cells arise by spontaneous mutations that occur randomly prior to exposition to copper sulphate. The rate of spontaneous mutation from copper sensitivity to resistance was 1.76 x 10(-6) mutants per cell division. Resistant mutants exhibited a diminished fitness in the absence of copper sulphate, but only these variants were able to grow at Cu(2+) concentrations higher than 5.8 microM. In addition, copper-resistant cells were significantly smaller than wild-type ones. Warnings on the long-term consequences of repetitive algaecide treatments in water supplies are suggested.

Bacterial Toxins↗

PubMed1999

Biliary excretion of copper in LEC rat after introduction of copper transporting P-type ATPase, ATP7B.

Wilson's disease, an autosomal recessive disorder, is characterized by the excessive accumulation of hepatic copper that results from reduced biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. The ATP7B gene, responsible for the disease, encodes a copper transporting P-type ATPase. We previously demonstrated the involvement of ATP7B in hepatic copper secretion into plasma after the introduction of ATP7B into the Long-Evans Cinnamon (LEC) rat, a rodent model of Wilson's disease. In this study we found the increased copper contents of the hepatic lysosomal fractions and bile in the LEC rats after ATP7B introduction, indicating the participation of ATP7B in the biliary excretory pathway for copper.

Adenosine Triphosphatases↗

PubMed1997

Copper supplementation of adult men: effects on blood copper enzyme activities and indicators of cardiovascular disease risk.

In rats, copper deficiency leads to low copper metalloenzyme activity, high serum cholesterol, and cardiovascular lesions. In humans, moderately low copper intake may be common, but the consequences remain largely uncertain. The present study examined the effects of copper supplementation (2 mg/d for 4 weeks in a copper/placebo crossover design) in 20 adult men with moderately high plasma cholesterol. End-point measurements were three copper enzyme activities, erythrocyte superoxide dismutase (SOD), plasma ceruloplasmin (Cp), and plasma diamine oxidase (DAO), and three parameters related to the risk of cardiovascular disease (CVD), plasma cholesterol, plasma lipoprotein (a) [Lp(a)], and lag times for very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) oxidation in vitro. Although copper had no significant effects on any parameter for the entire study group, it did significantly increase two enzyme activities (SOD and DAO), as well as lipoprotein oxidation lag times, in 10 subjects in the lower half of a median split for precopper values. Thus, copper supplementation appeared to influence some types of measurements in subjects beginning with less than median values.

Adult↗

PubMed1999

The relationship between soil copper content and copper resistance in yeast of an ultisol in midwestern Nigeria.

Yeast isolates were obtained from the brewer's stock of the Guinness brewery in Benin City, midwestern Nigeria, and from local sources such as mango and sugar cane. The fruits were exposed to the immediate soil environment in eleven selected sites in the Ugbowo and Ikpoba Hill areas of Benin City, Edo State of midwestern Nigeria. A total of twenty-seven yeast isolates were obtained. Fourteen isolates were identified as Saccharomyces cerevisiae and 13 as S. carlsbergensis. Analysis of resistance to copper sulphate revealed that the two brewer's yeast isolates were resistant to 3.5 mM and 4.2 mM CuSO4, respectively, while the local yeasts were resistant to higher concentrations ranging from 6.5 to 16.5 mM. The percentage copper sulphate resistance of yeast isolates obtained from Mangifera inidica ranged from 52.4 to 73.8%, while the percentage copper sulphate resistance of yeast isolates obtained from Saccharum officinarum ranged from 51.8 to 62.6%. The two brewer's yeast isolates (BY2 and BY4) had a percentage CuSO4 resistance of 32.4 and 38.5%, respectively. Comparison of soil copper concentration and copper resistance levels in selected yeast isolates indicated that the soil copper concentrations generally influenced the ability of yeasts to resist copper.

Beer↗

PubMed1997

CopY is a copper-inducible repressor of the Enterococcus hirae copper ATPases.

The cop operon of Enterococcus hirae effects copper homeostasis in this organism. It encodes a repressor, CopY, an activator, CopZ, and two P-type copper ATPases, CopA and CopB. Expression of all four genes is regulated by the ambient copper. In this regulation, CopY apparently acts as a copper-inducible repressor. By DNase I footprinting, it was shown that purified CopY protected two discrete sites in the region encompassing nucleotides -71 to -11 relative to the translational start site and containing hyphenated inverted repeats. Transcription is initiated between these repeats at nucleotide -42, in a domain that remained accessible to DNase I in the DNA-repressor complex. Chemical cross-linking revealed that CopY exists as a dimer in solution. In DNA band-shift assays, it was apparent that the CopY-DNA interaction occurred in two discrete steps. Half-maximal binding of repressor to the two operator sites was observed at 2 x 10(-9) M and 5 x 10(-9) M CopY, respectively. Copper ions released CopY from the promoter/operator with an apparent half-binding constant for Cu(I) of 20 microM. The site-directed mutations A-61T and A-30T essentially abolished the binding of CopY to the respective binding sites, and the double mutation A-61T/A-30T inactivated both binding sites. Thus, CopY is a copper-inducible repressor of the cop operon of E. hirae, exhibiting highly specific DNA-protein interactions with two sites on the cop promoter/operator and playing a key role in copper homeostasis in E. hirae.

Adenosine Triphosphatases↗

PubMed2000

Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2.

The Atx1 metallochaperone protein is a cytoplasmic Cu(I) receptor that functions in intracellular copper trafficking pathways in plants, microbes, and humans. A key physiological partner of the Saccharomyces cerevisiae Atx1 is Ccc2, a cation transporting P-type ATPase located in secretory vesicles. Here, we show that Atx1 donates its metal ion cargo to the first N-terminal Atx1-like domain of Ccc2 in a direct and reversible manner. The thermodynamic gradient for metal transfer is shallow (K(exchange) = 1.4 +/- 0.2), establishing that vectorial delivery of copper by Atx1 is not based on a higher copper affinity of the target domain. Instead, Atx1 allows rapid metal transfer to its partner. This equilibrium is unaffected by a 50-fold excess of the Cu(I) competitor, glutathione, indicating that Atx1 also protects Cu(I) from nonspecific reactions. Mechanistically, we propose that a low activation barrier for transfer between partners results from complementary electrostatic forces that ultimately orient the metal-binding loops of Atx1 and Ccc2 for formation of copper-bridged intermediates. These thermodynamic and kinetic considerations suggest that copper trafficking proteins overcome the extraordinary copper chelation capacity of the eukaryotic cytoplasm by catalyzing the rate of copper transfer between physiological partners. In this sense, metallochaperones work like enzymes, carefully tailoring energetic barriers along specific reaction pathways but not others.

Biological Transport↗

PubMed2001

The regulation of catalytic activity of the menkes copper-translocating P-type ATPase. Role of high affinity copper-binding sites.

The Menkes protein is a transmembrane copper translocating P-type ATPase. Mutations in the Menkes gene that affect the function of the Menkes protein may cause Menkes disease in humans, which is associated with severe systemic copper deficiency. The catalytic mechanism of the Menkes protein, including the formation of transient acylphosphate, is poorly understood. We transfected and overexpressed wild-type and targeted mutant Menkes protein in yeast and investigated its transient acyl phosphorylation. We demonstrated that the Menkes protein is transiently phosphorylated by ATP in a copper-specific and copper-dependent manner and appears to undergo conformational changes in accordance with the classical P-type ATPase model. Our data suggest that the catalytic cycle of the Menkes protein begins with the binding of copper to high affinity binding sites in the transmembrane channel, followed by ATP binding and transient phosphorylation. We propose that putative copper-binding sites at the N-terminal domain of the Menkes protein are important as sensors of low concentrations of copper but are not essential for the overall catalytic activity.

Adenosine Triphosphatases↗

PubMed2005

A single PDZ domain protein interacts with the Menkes copper ATPase, ATP7A. A new protein implicated in copper homeostasis.

The homeostatic regulation of essential elements such as copper requires many proteins whose activities are often mediated and tightly coordinated through protein-protein interactions. This regulation ensures that cells receive enough copper without intracellular concentrations reaching toxic levels. To date, only a small number of proteins implicated in copper homeostasis have been identified, and little is known of the protein-protein interactions required for this process. To identify other proteins important for copper homeostasis, while also elucidating the protein-protein interactions that are integral to the process, we have utilized a known copper protein, the copper ATPase ATP7A, as a bait in a yeast two-hybrid screen of a human cDNA library to search for interacting partners. One of the ATP7A-interacting proteins identified is a novel protein with a single PDZ domain. This protein was recently identified to interact with the plasma membrane calcium ATPase b-splice variants. We propose a change in name for this protein from PISP (plasma membrane calcium ATPase-interacting single-PDZ protein) to AIPP1 (ATPase-interacting PDZ protein) and suggest that it represents the protein that interacts with the class I PDZ binding motif identified at the ATP7A C terminus. The interaction in mammalian cells was confirmed and an additional splice variant of AIPP1 was identified. This study represents an essential step forward in identifying the proteins and elucidating the network of protein-protein interactions involved in maintaining copper homeostasis and validates the use of the yeast two-hybrid approach for this purpose.

Adenosine Triphosphatases↗