Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copper is an essential cofactor for approximately a dozen cuproenzymes in which copper is bound to specific amino acid residues in an active site. However, free cuprous ions react readily with hydrogen peroxide to yield the deleterious hydroxyl radical. Therefore, copper homeostasis is regulated very tightly, and unbound copper is extremely low in concentration. Copper imported by the plasma membrane transport protein Ctr1 rapidly binds to intracellular copper chaperone proteins. Atox1 delivers copper to the secretory pathway and docks with either copper-transporting ATPase ATP7B in the liver or ATP7A in other cells. ATP7B directs copper to plasma ceruloplasmin or to biliary excretion in concert with a newly discovered chaperone, Murr1, the protein missing in canine copper toxicosis. ATP7A directs copper within the transgolgi network to the proteins dopamine beta-monooxgenase, peptidylglycine alpha-amidating monooxygenase, lysyl oxidase, and tyrosinase, depending on the cell type. CCS is the copper chaperone for Cu,Zn-superoxide dismutase; it delivers copper in the cytoplasm and intermitochondrial space. Cox17 delivers copper to mitochondria to cytochrome c oxidase via the chaperones Cox11, Sco1, and Sco2. Other copper chaperones may exist and might include metallothionein and amyloid precursor protein (APP). Genetic and nutritional studies have illustrated the essential nature of these copper-binding proteins; alterations in their levels are associated with severe pathology.
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PMID:Intracellular copper transport in mammals. 1511 35

The limits of copper homeostatic regulation in humans are not known, making it difficult to define the milder effects of early copper excess. Furthermore, a robust assay to facilitate the detection of early stages of copper excess is needed. To address these issues, we assessed changes in relative mRNA abundance of methallothionein 2A (MT2A), prion (PrP), amyloid precursor-like protein 2 (APLP2), Cu/Zn superoxide dismutase (SOD1) and its copper chaperone (CCS) in peripheral mononuclear cells (PMNCs) from healthy adults representing the 5% highest and lowest extremes in the distribution curve of serum ceruloplasmin (Cp) concentrations of 800 individuals. The intracellular Cu content was also determined. PMNCs were isolated from individuals before and after exposure to a single daily dose of 10 mg Cu (as CuSO(4)) for 2 months. Results showed that although there were fluctuations in serum Cp values of the samples assessed before copper exposure, no significant differences were observed in cell copper content or in the relative abundance of MT2A, PrP and APLP2 transcripts in PMNCs. Also, these values were not modified after copper supplementation. However, CCS and SOD1 mRNA levels were reduced in PMNCs after copper supplementation in the individuals with the high Cp values, suggesting that they should be further explored as biomarkers of moderate copper overload in humans.
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PMID:CCS and SOD1 mRNA are reduced after copper supplementation in peripheral mononuclear cells of individuals with high serum ceruloplasmin concentration. 1768 25

The essentiality of copper (Cu) in humans is demonstrated by various clinical features associated with deficiency, such as anaemia, hypercholesterolaemia and bone malformations. Despite significant effort over several decades a sensitive and specific Cu status biomarker has yet to be identified. The present article updates a comprehensive review recently published by the authors which assesses the reliability and robustness of current biomarkers and outlines the on-going search for novel indicators of status(1). The essential features of this earlier review are reiterated whilst considering whether there are other approaches, not yet tested, which may provide valuable information in the quest for an appropriate measure of copper status. Current biomarkers include a range of cuproenzymes such as the acute phase protein caeruloplasmin and Cu-Zn-superoxide dismutase all of which are influenced by a range of other dietary and environmental factors. A recent development is the identification of the Cu chaperone, CCS as a potential biomarker; although its reliability has yet to be established. This appears to be the most promising potential biomarker, responding to both Cu deficiency and excess. The potential for identifying a 'suite' of biomarkers using high-throughput technologies such as transcriptomics and proteomics is only now being examined. A combination of these technologies in conjunction with a range of innovative metal detection techniques is essential if the search for robust copper biomarkers is to be successful.
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PMID:Biomarkers of copper status: a brief update. 1859 83

Copper is a redox active metal that is essential for biological function. Copper is potentially toxic; thus, its homeostasis is carefully regulated through a system of protein transporters. Copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1. Cupric ion may also be taken up, but those processes are less well understood. Within the cell, intestinal as well as others, copper is escorted to specific compartments by metallochaperones. One, CCS, donates copper to superoxide dismutase. Another, COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase. A third chaperone, Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases. One, ATP7A, is the protein nonfunctional in Menkes disease. This protein is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood. The second, ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion. Mutations in ATP7B lead to Wilson disease. Additional intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for excretion. Other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein. Plasma protein transport of copper from the intestine to liver and in systemic circulation probably includes both albumin and alpha2-macroglobulin. Changes in the expression of copper "transporters" may be useful to monitor copper status of humans, provided a suitable cell type can be sampled.
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PMID:Role of copper transporters in copper homeostasis. 1877 2

Serum or plasma copper and ceruloplasmin concentrations are the most widely used laboratory indicators to evaluate copper status. Both indicators are decreased in moderate or severe copper deficiency. The activity of several cuproenzymes is decreased in mild copper deficiency. However, their use is limited by the nonexistence of standardized assays and high interindividual variability and because some of these indicators are affected by other conditions. Recently, it was shown that the protein expression of the copper chaperone for superoxide dismutase (CCS) is increased in erythrocytes of rodents with mild copper deficiency. However, no traditional laboratory indicators have been identified as potential early markers of copper excess. It is possible that the biomarkers studied so far are not sensitive enough to detect an increase in body copper before the appearance of functional or clinical effects or that the homeostatic mechanisms are so strong that no significant changes in body copper occur with mild-to-moderate copper exposure. The identification of appropriate biomarkers for early detection of an increase in body copper represents a major challenge for further research, and the development of new approaches, such as network biology, allows us to search and propose new candidates to be studied. Recently, we found that CCS mRNA abundance in mononuclear blood cells significantly decreased after copper supplementation. The usefulness of this indicator to detect an increase in body copper should be assessed in clinical trials.
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PMID:Present situation of biomarkers for copper status. 1877 9

There is increased incidence of human copper deficiency (CuD). A sensitive and reliable blood biomarker may reveal additional cases of marginal deficiency. Two experiments were designed to test the hypothesis that the copper chaperone for superoxide dismutase (CCS) would be a robust marker after marginal CuD. Experiment 1 used weanling male Sprague-Dawley rats that were offered a CuD diet for 4 weeks, and samples were evaluated after 1, 2, and 4 weeks and compared with copper-adequate (CuA) controls. Furthermore, iron-deficient rats were included for comparison after 2 weeks of depletion. Red blood cell and plasma cuproenzymes were evaluated through Western blot analysis. Superoxide dismutase (Sod1) and ceruloplasmin protein were found to be altered by both iron and CuD, whereas CCS and CCS/Sod1 ratio were found to only be altered only in CuD rats and, importantly, after only 1 week of treatment. Two weeks on CuA diet restored cuproenzyme levels to control values after 4 weeks of CuD depletion. In experiment 2, marginal CuD (CuM) rats were compared with CuA and CuD rats after 2 weeks of treatment. Superoxide dismutase, ceruloplasmin, and CCS/Sod1 abundances were lower in CuM and CuD groups compared with CuA rats, but there was no statistical difference between CuM and CuD rats. However, CCS was statistically different between all groups, and abundance highly correlated with liver copper concentration. Results suggest that red blood cell CCS may be an excellent biomarker for diagnosis of rapid and marginal CuD.
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PMID:Rapid alteration in rat red blood cell copper chaperone for superoxide dismutase after marginal copper deficiency and repletion. 2202 94

The tolerable upper intake levels (UL) for zinc for children were based on limited data and there is concern that the UL may be set too low. The first effect of excessive zinc intake is a reduction in copper status. The primary objective of this study was to examine the effect of zinc supplementation on copper status in children. Healthy, 6- to 8-y-old boys from Ontario, Canada were assigned to take a placebo (n = 10) or 5 mg (n = 10), 10 mg (n = 9), or 15 mg (n = 8) of zinc supplement daily for 4 mo in a double-blinded, placebo-controlled, randomized trial. Biochemical measures were evaluated at baseline and after 2 and 4 mo of supplementation. Food records were completed near the baseline and 4-mo visits. Age and anthropometric measurements did not differ (P > 0.05) between treatment groups at baseline. Mean zinc intakes from food alone (10.9-14.8 mg zinc/d) approached or exceeded the UL of 12 mg/d. Compared with the placebo group, the zinc groups had a greater change in the urine zinc:creatinine ratio at 4 mo (P = 0.02). Traditional (plasma copper and ceruloplasmin activity) and more sensitive biomarkers of copper status, including erythrocyte SOD1 activity and the erythrocyte CCS:SOD1 protein ratio, were unchanged in zinc-supplemented boys, demonstrating that copper status was not depressed. Serum lipid measures and hemoglobin concentrations were also unaffected and gastrointestinal symptoms were not reported. These data provide evidence in support of the need for reexamining the current UL for zinc for children.
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PMID:Zinc supplementation does not alter sensitive biomarkers of copper status in healthy boys. 2330 74

Progressive functional maturation of spermatozoa is completed during the transit of these cells through the epididymis, a tubule structure connecting a testicle to a vas deferens. Epididymal epithelial cells by means of their secretory and absorptive functions determine a highly specialized luminal microenvironment containing multiple organic and inorganic components. The latter include copper ions, which due to their redox properties are indispensable for critical homeostatic processes occurring in spermatozoa floating in different part of epididymis but can be potentially toxic. Main purpose of our study was to determine epididymal region-dependent expression and localization of copper transporters ensuring a tight control of copper concentration in epididymal fluid. We also aimed at identifying proteins responsible for copper uptake by spermatozoa and verifying whether this process is coordinated with copper supply to superoxide dismutase 1 (SOD1), a copper-dependent antioxidant enzyme. Our study identifies two ATPases-ATP7A, ATP7B and Slc31a1, major copper importers/exporters depending on their differential expression on epididymal polarized epithelial cells of the caput, corpus, and cauda. Next, ceruloplasmin seems to be a chief protein transporting copper in the epididymal fluid and providing this biometal to spermatozoa. The entry of copper to germ cells is mediated by Slc31a1 and is correlated with both expressions of copper chaperone for superoxide dismutase (CCS), copper chaperone directly providing copper ions to SOD1 and with the expression and activity of the latter. Our results outline a network of cooperating copper binding proteins expressed in epididymal epithelium and in spermatozoa that orchestrate bioavailability of this microelement for gametes and protect them against copper toxicity.
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PMID:Molecular machinery providing copper bioavailability for spermatozoa along the epididymial tubule in mouse. 3099 85

Wilson's disease is characterized by hepatic and extrapyramidal movement disorders (EPS) with variable manifestation primarily between age 5 and 45. This variability often makes an early diagnosis difficult. A classification defines different clinical variants of Wilson's disease, which enables classifying the current clinical findings and making an early tentative diagnosis. Until the unequivocal proof or an autosomal recessive disorder of the hepatic copper transporter ATP7B has been ruled out, differential diagnoses have to be examined. Laboratory-chemical parameters of copper metabolism can both be deviations from the norm not related to the disease as well as other copper metabolism disorders besides Wilson's disease. In addition to known diseases such as Menkes disease, occipital horn syndrome (OHS), Indian childhood cirrhosis (ICC) and ceruloplasmin deficiency, recently discovered disorders are taken into account. These include MEDNIK syndrome, Huppke-Brendel syndrome and CCS chaperone deficiency. Another main focus is on differential diagnoses of childhood icterus correlated with age and anaemia as well as disorders of the extrapyramidal motor system. The Kayser-Fleischer ring (KFR) is qualified as classical ophthalmologic manifestation. The recently described manganese storage disease presents another rare metabolic disorder with symptoms similar to Wilson's disease. As this overview shows, Wilson's disease fits into a broad spectrum of internal and neurological disease patterns with icterus, anaemia and EPS.
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PMID:Classification and differential diagnosis of Wilson's disease. 3117

Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu⁺ from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu⁺ can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.
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PMID:The molecular mechanisms of copper metabolism and its roles in human diseases. 3250 22


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