Characterisation of the copper uptake mechanism and isolation of the ceruloplasmin receptor/copper transporter in human placental vesicles

Hilton, M D; Spenser, D.C; Ross, P. E.; Ramsey, Alexandra; McArdle, Harry J

doi:10.1016/0304-4165(95)00084-o

Cited by 30 publications

(18 citation statements)

References 24 publications

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“…The uptake was saturable and inhibited by zinc, albumin and N ‐ethylmaleimide. Hilton et al (1995) investigated the role of the ceruloplasmin receptor in vesicles prepared from human placental tissue, and suggested that uptake of copper from the bis‐histidine complex involved binding sites on this receptor. This receptor does not appear to correspond to any of the ‘ceruloplasmin receptors’ previously reported in erythrocytes, but the authors suggested that it was similar to the previously described receptor from liver endothelium.…”

Section: Discussionmentioning

confidence: 99%

Histidine‐stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7

Oakley

Horn

Thomas

2004

The Journal of Physiology

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The uptake of 65 Zn by human erythrocytes was investigated in the presence of high (40 mM) and low (5 mM) concentrations of histidine and 0-500 µM cobalt, nickel, manganese and zinc. Varying concentrations of metal mono-and bis-histidine complexes will be formed and the inhibition of 65 Zn uptake could be correlated with the calculated complex concentrations to investigate competition between metals. For each metal, the calculated concentrations of bis-histidine complex giving 50% inhibition of 65 Zn uptake were similar at both 5 mM and 40 mM histidine. Manganese-bis-histidine appeared to have a much higher affinity for the binding site than the other metal-bis-histidine complexes, which had similar affinities to each other. Studies of the inhibition of histidine-stimulated 54 Mn uptake by the addition of manganese confirmed that manganese-bis-histidine does act as a substrate for the transporter in a similar fashion to the other metals studied. In addition, human erythroleukaemic cells (HEL cells) were used as a model for erythroid precursor cells. L-histidine, but not D-histidine, stimulated 65 Zn uptake in a saturable fashion. The other metals competed with zinc in a similar manner to that seen in erythrocytes, and the affinity for manganese-bis-histidine was much greater than for the bis-histidine complexes of the other three metals. Both the capacity for metal transport per cell, and the affinity of the transporter for the metal-bis-histidine complexes, were much greater in the HEL cells than in the erythrocyte. It is suggested that histidine-stimulated metal transport may play a role in the supply of metals to maturing erythroid cells. The normal zinc concentration in human blood plasma is approximately 15 µm. Of this total, about one-third is incorporated within metalloproteins such as α 2 -macroglobulin and is not exchangeable with other plasma components (Giroux, 1975). The remaining zinc is labile and forms possible substrates for cellular uptake mechanisms. Approximately 3% of the total plasma zinc is in the form of coordination complexes formed between zinc, histidine and cysteine (Prasad & Oberleas, 1970;Harris & Keen, 1989). These are in a dynamic equilibrium with free ionic zinc and zinc bound to serum albumin. We have previously investigated the possible role of this amino acid-bound fraction in cellular zinc uptake into human erythrocytes. We reported that l-histidine increased 65 Zn uptake into both rat and human erythrocytes in a dose-dependent fashion, and that the rate of uptake correlated with the calculated concentration of the zinc-bis-histidine complex but not that of the zinc-mono-histidine complex or of free ionic zinc. Stimulation was only seen with the l-enantiomer; d-histidine simply acted as a chelator and reduced uptake. In these experiments, bovine serum albumin (BSA) was present as a metal ion buffer to maintain a low free ionic metal activity even at lower histidine concentrations (Horn et al. 1995). We also reported that the uptake of 109 Cd was stimulated by histidine conce...

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Section: Discussionmentioning

confidence: 99%

Histidine‐stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7

Oakley

Horn

Thomas

2004

The Journal of Physiology

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“…It plays a critical role in iron release from the liver (see Section 2.3.3), but has also been proposed as a copper delivery mechanism. Putative ceruloplasmin receptors have been identified in various tissues (Hilton et al, 1995;Sasina et al, 2000), but the protein has never been isolated and therefore its mechanism has not yet been elucidated.…”

Section: Transport In Bloodmentioning

confidence: 99%

Scientific Opinion on Dietary Reference Values for copper

Products¹

2015

EFSA Journal

137

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Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for copper. Owing to the absence of appropriate biomarkers of copper status and the limitations of available balance studies, the Panel was unable to derive Average Requirements (ARs) and Population Reference Intakes (PRIs). Hence, Adequate Intakes (AIs) were defined based on mean observed intakes in several European Union (EU) countries, given that there is no evidence of overt copper deficiency in the European population. Data from balance studies were used as supportive evidence. For adults, AIs of 1.6 mg/day for men and 1.3 mg/day for women are proposed. For children, AIs are 0.7 mg/day for children aged 1 to < 3 years, 1 mg/day for children aged 3 to < 10 years, and 1.3 and 1.1 mg/day for boys and girls aged 10 to < 18 years, respectively. For infants aged 7-11 months, based on mean observed intakes in four EU countries, an AI of 0.4 mg/day is proposed, which is supported by upwards extrapolation of estimated copper intake in exclusively breast-fed infants. For pregnant women, an increment of 0.2 mg/day is estimated to cover the amount of copper deposited in the fetus and the placenta over the course of pregnancy and in anticipation of the needs for lactation, and for lactating women the same increment is estimated to cover the amount of copper secreted with breast milk. Thus, for pregnant and lactating women, the Panel derived an AI of 1.5 mg/day. Copper is an essential micronutrient required for electron transfer processes. It is a central component of many enzymes, including those involved in neurotransmitter synthesis, in energy metabolism and in collagen and elastin cross-linking.The main food group contributing to the copper intake of all population groups except infants is grains and grain-based products. Another important contributor to copper intake is the food group meat and meat products.Based on balance studies and other studies, the Panel considered that copper absorption from the diet is around 50 % for all age and life-stage groups.The primary site of copper absorption is the upper small intestine. Uptake is through a carrier protein, Ctr1, and once in the cell, the copper is directed towards its target via one of a series of chaperone proteins that ensure the metal is present in a non-toxic form. In the gut, the major pathway of transport into the portal circulation is via a Cu-ATPase, ATP7A. In the portal circulation, copper is bound to histidine, albumin or possibly transcuprein and transported to the liver, where it is incorporated into ceruloplasmin, which is then secreted into the systemic circulation. It is taken up into the liver through Ctr1 and, if it is not incorporated into ceruloplasmin, it is stored as metallothionein. Excess copper is excreted in bile after transport across the apical membrane of the hepatocytes via another ATPase, ATP7B. This copper is not reabsorbed. In humans, between 80 and 95 % of the copper in...

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“…When interacting with other proteins, CP can also acquire new functions. A number of studies describe the CP interaction with some proteins and peptides in vitro and suggest hypotheses on the role of these protein complexes in vivo [14][15][16][17][18][19][20][21][22][23]. For example, CP probably participates in the regulation of blood coagulation via competing with BCFs FV and FVIII for protein C binding [14].…”

Section: Introductionmentioning

confidence: 99%

“…The membrane-bound CP found in astrocytes [20] is involved in the regulation of iron level in central nervous system and prevention of free radical reactions due to complex formation with ferroportin I [21]. The interaction of CP with the membrane-bound placental alkaline phosphatase was also revealed [22], the role of this fact yet remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Isolation of Stable Human Ceruloplasmin and Its Interaction with Salmon Protamine

et al. 2005

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An interaction was discovered between ceruloplasmin (CP, a ferro-O2-oxidoreductase, EC 1.16.3.1), a copper-containing protein of human blood plasma, and salmon protamine (PR), a cationic polypeptide of vertebrates that provides a compact structure of spermatozoid DNA. Addition of PR to CP at a molar ratio of 2: 1 decreases the CP electrophoretic mobility. Two types of CP binding centers for PR were determined: two centers with a high (Kd1 of 5.31 x 10(-7) M) and four centers with a low affinity (Kd2 of 1.56 x 10(-5) M). PR was shown to form complexes with CPs of various animal species. The CP-PR complex dissociates at an increased ionic strength (0.3 M NaCl), at pH decreased below 4.7, or in the presence of added polyanions (DNA, lipopolysaccharides, or heparin) and/or polylysine, which indicates the electrostatic nature of the interaction. The CP-PR interaction increased 1.5-fold the rate of CP-catalyzed oxidation of Fe2+. The preliminary treatment of blood plasma with arginine-Sepharose and heparin-Sepharose (to remove the blood coagulation factors) and affinity chromatography on PR-Sepharose helped isolate the practically unproteolyzed monomeric CP in 90% yield; it remained stable for more than two months at 37 degrees C. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.

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Characterisation of the copper uptake mechanism and isolation of the ceruloplasmin receptor/copper transporter in human placental vesicles

Cited by 30 publications

References 24 publications

Histidine‐stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7

Histidine‐stimulated divalent metal uptake in human erythrocytes and in the erythroleukaemic cell line HEL.92.1.7

Scientific Opinion on Dietary Reference Values for copper

Isolation of Stable Human Ceruloplasmin and Its Interaction with Salmon Protamine

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