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PubMed2006

Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status.

Studies were conducted to determine distribution of the copper transporter, Ctr1, a transmembrane protein responsible for cellular copper uptake, in adult mice and in suckling mice nursed by either copper-adequate (Cu+) or copper-deficient (Cu-) dams. Western immunoblot analyses, using immunopurified antibody, detected monomeric (23 kDa) and oligomeric forms of Ctr1 in the membrane fraction of several mouse organs. Immunohistochemical analyses detected abundant Ctr1 protein in liver canaliculi; kidney cortex tubules; small intestinal enterocytes; the choroid plexus and capillaries of brain; intercalated disks of heart; mature spermatozoa; epithelium of mammary ducts; and the pigment epithelium, outer limiting membrane, and outer plexiform layer of the retina. Duodenal Ctr1 distribution was different in the adult compared with suckling mice; adult mice demonstrated strong intracellular staining of the enterocyte, whereas apical staining predominated in suckling mice. In Cu- mice at postnatal d 16 (P16), Ctr1 staining was augmented in kidney, duodenum, and choroid plexus, compared with Cu+ mice. Brain immunoblot data indicated that Ctr1 protein in membrane fractions of Cu- mice was 56% higher than Cu+ mice. Cu- mice had lower hemoglobin (56% of Cu+), and lower copper concentration (% of Cu+) in liver (15%), brain (26%), and kidney (65%). These results suggest that Ctr1 protein is expressed in multiple tissues and found in higher levels in selected organs after perinatal copper deficiency. Enhanced Ctr1 levels and redistribution might compensate in part for the decrease in copper supply. Mechanisms for the enhancement in Ctr1 staining remain to be established.

Animals↗

PubMedDate not supplied

Accumulation, distribution, and toxicity of copper in sediments of catfish ponds receiving periodic copper sulfate applications.

Copper sulfate (CuSO4) is applied periodically to commercial channel catfish (Ictalurus panctatus) ponds as an algicide or parasiticide. Current understanding of the chemistry of copper in soil-water systems suggests that copper may accumulate in pond sediments, although the forms and potential bioavailability of copper in catfish pond sediments are not known. This study investigated the accumulation and distribution of copper in the sediment of catfish ponds receiving periodic additions of CuSO4.5H2O. All ponds were constructed in Sharkey (very-fine, smectitic, thermic Chromic Epiaquert) soil. Nine 0.40-ha ponds received 59 applications of 2.27 kg CuSO4.5H2O per application per pond over 3 yr; no CuSO4.5H2O applications were made to nine additional ponds. Total Cu concentration in the sediments of CuSO4.5H2O-amended catfish ponds (172.5 mg kg(-1)) was four to five times higher than that in the sediments of nonamended ponds (36.1 mg kg(-1)). Copper accumulated in catfish pond sediments at a rate of 41 microg kg(-1) dry sediment for each 1 kg ha(-1) of CuSO4. 5H2O applied to ponds. Copper in the sediments of amended ponds was mainly in the organic matter-bound (30.7%), carbonate-bound (31.8%), and amorphous iron oxide-bound (22.1%) fractions with a considerable fraction (3.4%; 3 to 8 mg kg(-1)) in soluble and exchangeable fractions. This indicates that Cu accumulates differentially in various fractions, with proportionally greater initial accumulation in potentially bioavailable forms. However, toxicity bioassays with amphipods (Hyallela azteca) and common cattail (Typha latifolia L.) indicated that the effect of exposure to amended or nonamended pond sediments was not different.

Animals↗

PubMed1985

Effects of copper sulfate supplement on growth, tissue concentration, and ruminal solubilities of molybdenum and copper in sheep fed low and high molybdenum diets.

Each of four groups of six wethers were fed one of a low molybdenum, high molybdenum, low molybdenum plus copper sulfate, or high molybdenum plus copper sulfate corn silage-based diet for ad libitum intake for 221 days. Average daily gains and ratios of feed/gain were depressed for the high molybdenum diet as compared with the low molybdenum diet suggesting molybdenum toxicity in sheep fed the high molybdenum diet. This was alleviated partly by the copper sulfate supplement. The supplement also decreased solubility of both copper and molybdenum in the rumen but had no effect on copper concentration in blood plasma. Concentration of molybdenum was higher in both liver and kidney in sheep fed high-molybdenum diets as compared with low-molybdenum diets. Copper concentration was higher in kidneys of sheep fed high-molybdenum diets, but no difference was significant in liver copper between sheep fed diets high or low in molybdenum.

Animals↗

PubMed1990

Copper uptake in wild type and copper metallothionein-deficient Saccharomyces cerevisiae. Kinetics and mechanism.

The mechanism of copper uptake in Saccharomyces cerevisiae has been investigated using a combination of 64Cu2+ and atomic absorption spectrophotometry. A wild type copper-resistant CUP 1R-containing strain and a strain carrying a deletion of the CUP1 locus (yeast copper metallothionein) exhibited quantitatively similar saturable energy-dependent 64Cu2+ uptake when cultures were pregrown in copper-free media (medium [Cu] approximately 15 nM). The kinetic constants for uptake by the wild type strain were Vmax = 0.21 nmol of copper/min/mg of protein and Km = 4.4 microM. This accumulation of 64Cu2+ represented net uptake as confirmed by atomic absorption spectrophotometry. This uptake was not seen in glucose-starved cells, but was supported in glycerol- and ethanol-grown ones. Uptake was inhibited by both N3- and dinitrophenol and was barely detectable in cultures at 4 degrees C. When present at 50 microM, Zn2+ and Ni2+ inhibited by 50% indicating that this uptake process was relatively selective for Cu2+. 64Cu2+ accumulation was qualitatively and quantitatively different in cultures either grown in or preincubated with cold Cu2+. Either treatment resulted in the appearance of a fast phase (t 1/2 approximately 1 min) of 64Cu2+ accumulation which represented isotopic exchange since it did not lead to an increase in the mass of cell-associated copper; also, it was not energy-dependent. Exchange of 64Cu2+ into this pool was not inhibited by Zn2+. Pretreatment with Cu2+ caused a change in the rate of net accumulation as well; a 3-h incubation of cells in 5 microM medium Cu2+ caused a 1.6-fold increase in the velocity of energy-dependent uptake. Prior addition of cycloheximide abolished this Cu2(+)-dependent increase and, in fact, inhibited the 64Cu2+ uptake velocity by greater than 85%. The exchangeable pool was also absent in cycloheximide, Cu2(+)-treated cells suggesting that exchangeable Cu2+ derived from the copper taken up initially by the energy-dependent process. The thionein deletion mutant was similar to wild type in response to medium Cu2+ and cycloheximide indicating that copper metallothionein is not directly involved in Cu2+ uptake (as distinct from retention) in yeast.

Azides↗

PubMed1980

Copper proteins and copper enzymes.

The copper proteins that function in homeostasis, electron transport, dioxygen transport and oxidation are discussed. Particular emphasis is placed on the role of the ligands, their type and disposition which, in conjunction with other residues in the active site, determine the role of the copper ion. It is proposed that copper proteins can be considered in four groups. Those in Group I contain a single copper ion in an approximately tetrahedral environment with nitrogen and sulphur-containing ligands. Group II proteins have a single copper ion in a square-planar-like arrangement. Group III proteins have two copper ions in close proximity. Group IV consists of multi-copper proteins, composed of sites representative of the other three groups.

Animals↗

PubMed1999

Copper and signal transduction: platelets as a model to determine the role of copper in stimulus-response coupling.

Platelets from copper-deficient rats have been used as a model to investigate the role of copper in receptor-mediated cellular responses. Copper deficiency doubles the rate of dense granule secretion and increases myosin association with the platelet cytoskeleton following thrombin stimulation. Mechanisms underlying the effects of copper deficiency on thrombin-induced signals that elicit dense granule secretion involve suppression of protein kinase C activity and impairment of Ca2+ release from intracellular stores. Copper deficiency also reduces the cellular GTP content of platelets. This may limit receptor effector coupling through GTP-dependent regulatory proteins leading to protein kinase C activation and the release of Ca2+ from intracellular stores. The reduction in GTP content during copper deficiency results from its utilization to maintain cellular ATP levels in response to severely inhibited cytochrome c oxidase activity in platelet mitochondria. Thus, the role of copper in maintaining normal signal transduction may be indirectly related to its biological function in mitochondria.

Animals↗

PubMed1988

The physiological role of copper and the problems of copper nutritional deficiency.

The paper deals with recent achievements concerning the physiological role of copper in the human organism. The problem of copper supplementation of the human diet is discussed. An outlook is given on the contemporary theories referring to the role of copper in nutrition. Special attention has been paid to the copper-containing enzymes and copper-dependent enzymes as well as to the problem of nutritional copper deficiencies. This paper shows the necessity of copper for: --"cleaning" of the organism from the excesses of free radicals, biogenic amines and cholesterol --the proper synthesis of hemoglobin, elastin, collagen and probably thyroid hormones --providing the energy formed in the respiratory chain and needed for biochemical syntheses and proper physical activity.

Animals↗

PubMed2000

Copper-mediated toxicity of 2,4,5-trichlorophenol: biphasic effect of the copper(I)-specific chelator neocuproine.

The lipophilic copper(I)-specific chelator neocuproine has been frequently used as an inhibitor of copper-mediated damage in biological systems. In this communication we report that the copper-mediated toxicity of 2,4,5-trichlorophenol is markedly potentiated by neocuproine at levels which are near-stoichiometric with respect to the copper concentration but is inhibited at higher concentrations. However, no potentiation was observed when neocuproine was substituted by bathocuproinedisulfonic acid, a negative charged ligand with essentially the same copper-binding characteristics as neocuproine. We found that the potentiation by neocuproine was due to the formation of a lipophilic copper complex, while the inhibition by bathocuproinedisulfonic acid was due to the formation of a hydrophilic one. Caution in the use of neocuproine to study copper-mediated toxicity is advised.

Catalase↗

PubMed2001

Interaction of the CopZ copper chaperone with the CopA copper ATPase of Enterococcus hirae assessed by surface plasmon resonance.

Intracellular copper routing in Enterococcus hirae can be accomplished by the CopZ metallochaperone. Using surface plasmon resonance analysis, we show here that CopZ interacts with the CopA copper ATPase. The binding affinity of CopZ for CopA was increased in the presence of copper, due to a 15-fold lower dissociation rate constant. Mutating the N-terminal copper binding motif of CopA from CxxC to SxxS abolished this copper-induced effect. Moreover, CopZ failed to show an interaction with an unrelated copper binding protein used as a control. These results show that (i) the CopA copper ATPase specifically interacts with the CopZ chaperone, (ii) this interaction is based on protein-protein interaction, and (iii) surface plasmon resonance is a novel tool for quantitative analysis of metallochaperone-target interactions.

Adenosine Triphosphatases↗

PubMed2002

Copper inhibits activated protein C: protective effect of human albumin and an analogue of its high-affinity copper-binding site, d-DAHK.

Activated protein C (APC) is useful in the treatment of sepsis. Ischemia and acidosis, which often accompany sepsis, cause the release of copper from loosely bound sites. We investigated (i) whether physiological concentrations of copper inhibit APC anticoagulant activity and (ii) if any copper-induced APC inhibition is reversible by human serum albumin (HSA) or a high-affinity copper-binding analogue of the human albumin N-terminus, d-Asp-d-Ala-d-His-d-Lys (d-DAHK). APC activity after 30 min of incubation with CuCl2 (10 microM) was decreased 26% below baseline. HSA, both alone and when combined with various ratios of CuCl2, increased APC activity significantly above baseline. d-DAHK alone and 2:1 and 4:1 ratios of d-DAHK:CuCl2 also increased APC activity. APC contained 1.4 microM copper, which helps explain the increased APC activity with HSA and d-DAHK alone. These in vitro results indicate that copper inhibits APC activity and that albumin and d-DAHK reverse the copper-induced APC deactivation.

Binding Sites↗

PubMed1985

Excretion process of copper from copper pre-loaded rat liver parenchymal cells.

Excretion of copper from copper pre-loaded rat liver parenchymal cells was investigated. The copper pre-loaded cells were isolated from the liver of copper-administered rats and were maintained for 4 days in modified Williams medium E; sodium pyruvate was increased while calcium was reduced in concentration, and 10% fetal bovine serum and insulin were added. For the first 30 hr after plating, loss of copper was slow, with a half-life of more than 100 hr: subsequently the rate of loss was faster, with a half-life of 51 +/- 9 hr. Copper pre-loaded in the cells was mostly bound to metallothionein and the amount of copper-metallothionein decreased with time of culture. Furthermore, the relative ratio of the two iso-metallothioneins changed with length of culture.

Animals↗

PubMed1982

The distribution of copper in neonatal mottled mutant mice after exposure to copper and penicillamine.

Tissue copper levels of brindled (Mobr) mice and normal litter-mates after single and repeated dosing with CuCl2 and/or D-penicillamine are examined, together with a study of the cytosol distribution of copper after CuCl2 treatment. The results confirm that the mutant mouse kidney is capable of extensive copper accumulation in association with the low MW copper-binding protein. Deficient tissues such as brain, heart and spleen are able to sequester sufficient of the exogenous copper to raise their levels to the normal control level, whereas mutant liver levels, even after copper treatment, remain below normal, indicating that the Mo gene affects the ability of the liver to retain copper.

Animals↗

PubMed2006

The Cu(II)-reductase NADH dehydrogenase-2 of Escherichia coli improves the bacterial growth in extreme copper concentrations and increases the resistance to the damage caused by copper and hydroperoxide.

NADH dehydrogenase-2 (NDH-2) from Escherichia coli respiratory chain is a membrane-bound cupric-reductase encoded by ndh gene. Here, we report that the respiratory system of a ndh deficient strain suffered a faster inactivation than that of the parental strain in the presence of tert-butyl hydroperoxide due to endogenous copper. The inactivation was similar for both strains when copper concentration increased in the culture media. Furthermore, several ndh deficient mutants grew less well than the corresponding parental strains in media containing either high or low copper concentrations. A mutant strain complemented with ndh gene almost recovered the parental phenotype for growing in copper limitation or excess. Then, NDH-2 gives the bacteria advantages to diminish the susceptibility of the respiratory chain to damaging effects produced by copper and hydroperoxides and to survive in extreme copper conditions. These results suggest that NDH-2 contributes in the bacterial oxidative protection and in the copper homeostasis.

Copper↗

PubMed2006

Application of saccharose as copper(II) ligand for electroless copper plating solutions.

Saccharose, forming sufficiently stable complexes with copper(II) ions in alkaline solutions, was found to be a suitable ligand for copper(II) chelating in alkaline (pH>12) electroless copper deposition solutions. Reduction of copper(II)-saccharose complexes by hydrated formaldehyde was investigated and the copper deposits formed were characterized. The thickness of the compact copper coatings obtained under optimal operating conditions in 1h reaches ca. 2 microm at ambient temperature. The plating solutions were stable and no signs of Cu(II) reduction in the bulk solution were observed. Results were compared with those systems operating with other copper(II) ligands.

Chelating Agents↗

PubMed2006

Seasonal and spatial patterns of metals at a restored copper mine site II. Copper in riparian soils and Bromus carinatus shoots.

Soil and plants were sampled throughout winter and spring near a perennial stream traversing a restored mine site in a winter-rainy climate. Within 1m of an acidic reach of the stream, soil had pH 3-5 and 50-100 microg/g "bioavailable" copper (extractable with 0.01 M CaCl2). Soil 2-3 m from the stream had pH 5-8 and lower (less than 3 microg/g) bioavailable copper. "Oxide-bound" copper (extractable with 2N HCl) was 50-100 microg/g at most locations. Copper concentrations in the shoots of field-collected Bromus carinatus declined from 20 microg/g in winter to 2 microg/g in spring at all sampling sites. A similar temporal pattern was found in plants grown under controlled conditions. Thus B. carinatus has a developmental program for control of shoot copper concentration, causing a seasonally-varying pattern of copper phytoaccumulation over a large range of copper availability in the soil.

Biodegradation, Environmental↗

PubMed1988

Copper storage disease of the liver and chronic dietary copper intoxication in two further German infants mimicking Indian childhood cirrhosis.

A severe copper storage disease of the liver with micronodular cirrhosis resembling Indian childhood cirrhosis (ICC) was found in two siblings of a German family leading to death in one infant at the age of 13 months. The fatal outcome correlated with severe ballooning of hepatocytes and excessive formation of Mallory bodies. The copper content of the liver was 698 micrograms per gramme wet weight (control 5 micrograms) in the living patient and 2154 micrograms per gramme dry weight (controls 39, 54 micrograms) in the dead infant. In both cases copper was stored not only in hepatocytes but also to a high degree in mesenchymal cells. Chronic contamination of drinking water supplied from a well via copper pipes could be verified as the cause of copper intoxication, lending further support to ICC as an environmental, acquired disorder. Accumulation of exogenic copper already very early in infancy appears most important for the development of the disease, as both the parents and one child not exposed to copper intoxication during the first 9 months of its life are clinically healthy.

Chemical and Drug Induced Liver Injury↗

PubMed2002

Copper homeostasis and aging in the fungal model system Podospora anserina: differential expression of PaCtr3 encoding a copper transporter.

Lifespan extension of Podospora anserina mutant grisea is caused by a loss-of-function mutation in the nuclear gene Grisea. This gene encodes the copper regulated transcription factor GRISEA recently shown to be involved in the expression of PaSod2 encoding the mitochondrial manganese superoxide dismutase. Here we report the identification and characterization of a second target gene. This gene, PaCtr3, encodes a functional homologue of the Saccharomyces cerevisiae high affinity copper permease yCTR3. PaCtr3 is not expressed in the grisea mutant confirming the assumption that the extension of lifespan is primarily caused by cellular copper limitation and a switch from a cytochrome oxidase (COX)-dependent to and alternative oxidase (AOX)-dependent respiration. Transcript levels of PaCtr3 and PaSod2 respond to copper, iron, manganese and zinc. Transcription of PaCtr3 was found to be down-regulated during senescence of wild-type cultures suggesting that the intracellular copper concentration is raised in old cultures. A two hybrid analysis suggested that GRISEA acts as a homodimer. In accordance, an inverted repeat was identified as a putative binding sequence in the promoter region of PaCtr3 and of PaSod2. Finally, the expression of PaCtr3 in transformants of the grisea mutant led to lifespan shortening. This effect correlates with the activity of the copper-dependent COX demonstrating a strong link between copper-uptake, respiration and lifespan.

Aging↗

PubMed2005

Dioxygen reactivity of copper and heme-copper complexes possessing an imidazole-phenol cross-link.

Recent spectroscopic, kinetics, and structural studies on cytochrome c oxidases (CcOs) suggest that the histidine-tyrosine cross-link at the heme a3-CuB binuclear active site plays a key role in the reductive O2-cleavage process. In this report, we describe dioxygen reactivity of copper and heme/Cu assemblies in which the imidazole-phenol moieties are employed as a part of copper ligand LN4OH (2-{4-[2-(bis-pyridin-2-ylmethyl-amino)-ethyl]-imidazol-1-yl}-4,6-di -tert-butyl-phenol). Stopped-flow kinetic studies reveal that low-temperature oxygenation of [CuI(LN4OH)]+ (1) leads to rapid formation of a copper-superoxo species [CuII(LN4OH)(O2-)]+ (1a), which further reacts with 1 to form the 2:1 Cu:O2 adduct, peroxo complex [{CuII(LN4OH)}2(O2(2-))]2+ (1b). Complex 1b is also short-lived, and a dimer Cu(II)-phenolate complex [CuII(LN4O-)]2(2+) (1c) eventually forms as a final product in the later stage of the oxygenation reaction. Dioxygen reactivities of 1 and its anisole analogue [CuI(LN4OMe)]+ (2) in the presence of a heme complex (F8)FeII (3) (F8 = tetrakis(2,6,-difluorotetraphenyl)-porphyrinate) are also described. Spectroscopic investigations including UV-vis, 1H and 2H NMR, EPR, and resonance Raman spectroscopies along with spectrophotometric titration reveal that low-temperature oxygenation of 1/3 leads to formation of a heme-peroxo-copper species [(F8)FeIII-(O2(2-))-CuII(LN4OH)]+ (4), nu(O-O) = 813 cm(-1). Complex 4 is an S = 2 spin system with strong antiferromagnetic coupling between high-spin iron(III) and copper(II) through a bridging peroxide ligand. A very similar complex [(F8)FeIII-(O2(2-))-CuII(LN4OMe)]+ (5) (nu(O-O) = 815 cm(-1)) can be generated by utilizing the anisole compound 2, which indicates that the cross-linked phenol moiety in 4 does not interact with the bridging peroxo group between heme and copper. This investigation thus reveals that a stable heme-peroxo-copper species can be generated even in the presence of an imidazole-phenol group (i.e., possible electron/proton donor source) in close proximity. Future studies are needed to probe key factors that can trigger the reductive O-O cleavage in CcO model compounds.

Copper↗