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)

We have examined the tissue uptake of 67Cu from ceruloplasmin versus albumin and transcuprein, after its intravenous administration to pregnant rats, in the last 4 days of gestation. 67Cu infused as in vivo-labeled ceruloplasmin remained on ceruloplasmin in the maternal circulation over the 4- to 6-hr time period examined, as determined by gel chromatography and immunoreactivity. That infused as in vitro-labeled serum was initially on transcuprein and albumin but soon also with new ceruloplasmin. On the basis of percent dose as well as total actual Cu transferred (taking into account the sizes of the two plasma Cu pools), ceruloplasmin was the preferred source of Cu for most tissues. Total uptake of Cu from ceruloplasmin was seven times greater than that from albumin and transcuprein for the placenta, whole fetus, and fetal liver. It was 2- to 6-fold greater for other tissues (except liver and kidney). When synthesis of maternal 67Cu-ceruloplasmin (from 67Cu administered on albumin and transcuprein) was inhibited with cycloheximide, uptake by nonhepatic tissues was reduced markedly. In the fetal circulation, entering 67Cu was initially associated with transcuprein and alpha-fetoprotein (or albumin), but then also appeared with ceruloplasmin. Specific receptors for ceruloplasmin were detected on membranes from the placenta as well as fetal liver; mRNA for ceruloplasmin was detected on the endoplasmic reticulum-bound polyribosomes of placenta/yolk sac, and of fetal and maternal liver. We conclude that Cu destined for the fetus is delivered mainly or exclusively by ceruloplasmin. It may enter via placental receptors, arriving in fetal plasma in ionic form, for later incorporation into fetal ceruloplasmin. The importance of ceruloplasmin as a source of plasma Cu for nonhepatic organs is also confirmed.
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PMID:Ceruloplasmin and copper transport during the latter part of gestation in the rat. 839 86

The effects of estrogen on synthesis and turnover of ceruloplasmin were studied in adult female Fischer rats. Daily treatment with 140 microgram 17 beta-estradiol resulted in a slow rise of ceruloplasmin concentrations, as measured by p-phenylenediamine oxidase activity, leading to a 70% increase by 7 days and a tripling by Day 14. Ceruloplasmin protein concentrations increased to the same degree, based on yields of the protein obtained during purification. Effects of estrogen on rates of synthesis (incorporation of [3H]leucine) were followed, using immunoprecipitation of total ceruloplasmin or isolation of its two major isoforms (Rfs 0.4 and 0.6 in native gel electrophoresis). Synthesis was increased by 7 days and was 2.5 times that of controls by Day 14. Both forms of ceruloplasmin showed the same specific activities and degree of increase in rate of synthesis. Rates of ceruloplasmin turnover were unaffected, based on double labeling with 3H- and 14C-leucine, but were three- to fourfold faster than for total plasma protein. The enzymatically more active 0.6 Rf form of ceruloplasmin had a faster turnover rate than the 0.4 Rf form. Estrogen treatment doubled ceruloplasmin mRNA levels by 7 days and almost tripled them by Day 14. Most of the ceruloplasmin mRNA was associated with the endoplasmic reticulum-bound polyribosomes. We conclude that estrogen increases the rate of synthesis of two forms of ceruloplasmin by indirectly increasing liver concentrations of its mRNA but has no effect on ceruloplasmin turnover.
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PMID:Synthesis and turnover of ceruloplasmin in rats treated with 17 beta-estradiol. 848 41

We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, indicating that these ATP7B proteins retained copper transport activity. We analyzed the intracellular localization of these active WND ATP7B variant proteins using transient transfection of Chinese hamster ovary cells and triple-label immunofluorescence microscopy, as a second possible aspect of defective function. Two ATP7B variants, Asp765Asn and Leu776Val, which have normal copper transport activity in yeast, retained partial normal Golgi network localization, but were predominantly mislocalized throughout the cell. Asp765Asn and Leu776Val proteins were capable of only partial copper-dependent redistribution. WND variant protein Arg778Leu, which has defective function in yeast, was extensively mislocalized, presumably to the endoplasmic reticulum. ATP7B variant proteins Gly943Ser, which has nearly normal function in yeast, and CysProCys/Ser (mutation of the conserved CysProCys motif to SerProSer), inactive in yeast, were localized normally but were unable to redistribute in response to copper. Localization data from this study, combined with functional data from our yeast studies, provide a biochemical mechanism that can explain in part the variable biochemical features of WND, in particular the normal holo-ceruloplasmin levels observed in some patients. Our data have direct implications for WND diagnosis, indicating that decreased serum ceruloplasmin concentration is not likely to be observed with certain genetic variants of WND.
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PMID:Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. 1094 20

The mechanism of iron release from the placenta into the fetal circulation is not well understood. Ceruloplasmin, a plasma ferroxidase, has been implicated in iron efflux from a variety of cell types. The hypothesis is that circulating ceruloplasmin facilitates iron efflux by oxidizing the released Fe(II) to Fe(III) for incorporation into transferrin. We tested whether this mechanism mediates iron release from placental cells into the fetal circulation, using the BeWo cell line, a choriocarcinoma which can differentiate into a syncytium.(59)Fe release from undifferentiated or differentiated cells and from cells grown on porous filters was not stimulated by extracellular ceruloplasmin. Instead, we found that BeWo cells express an endogenous ferroxidase. The protein is membrane bound and cross-reacts with an anti-ceruloplasmin antibody, but has a different size; 100 and 140 kDa. Similar immunoreactivity was identified in first- and third-trimester human placentae. In BeWo cells, the protein has a perinuclear localization but does not entirely co-localize with markers for the endoplasmic reticulum or Golgi apparatus. We propose that this oxidase performs the same function as serum ceruloplasmin and is involved in iron release into the fetal circulation.
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PMID:The effect of ceruloplasmin on iron release from placental (BeWo) cells; evidence for an endogenous Cu oxidase. 1109 30

Aceruloplasminemia is an inherited neurodegenerative disease characterized by parenchymal iron accumulation secondary to loss-of-function mutations in the ceruloplasmin gene. To elucidate the molecular pathogenesis of aceruloplasminemia, the biosynthesis of a missense mutant ceruloplasmin (P177R) occurring in an affected patient was examined. Chinese hamster ovary cells transfected with cDNAs encoding secreted and glycosylphosphatidylinositol (GPI)-linked wild-type or P177R human ceruloplasmin were examined by pulse-chase metabolic labeling. These experiments, as well as immunofluorescent analysis and N-linked glycosylation studies, indicate that both the secreted and GPI-linked forms of the P177R mutant are retained in the endoplasmic reticulum (ER). The P177R mutation resides within a novel motif, which is repeated six times in human ceruloplasmin and is conserved in the homologous proteins hephaestin and factor VIII. Analysis of additional mutations in these motifs suggests a critical role for this region in ceruloplasmin trafficking and indicates that substitution of the arginine residue is critical to the ER retention of the P177R mutant. Metabolic labeling of transfected Chinese hamster ovary cells with (64)Cu indicates that the P177R mutant is retained in the ER as an apoprotein and that copper is incorporated into both secreted and GPI-linked ceruloplasmin as a late event in the secretory pathway. Taken together, these studies reveal new insights into the determinants of holoceruloplasmin biosynthesis and indicate that aceruloplasminemia can result from retention of mutant ceruloplasmin within the early secretory pathway.
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PMID:Biochemical analysis of a missense mutation in aceruloplasminemia. 1168 69

Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. More than 30 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.
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PMID:Molecular and pathological basis of aceruloplasminemia. 1662 61

Aceruloplasminemia is a neurodegenerative disease characterized by parenchymal iron accumulation owing to mutations in the ceruloplasmin gene. Ceruloplasmin is expressed in the central nervous system in which most of the ceruloplasmin is located on the surface of astrocytes in a glycosylphosphatidylinositol (GPI)-anchored form. We herein describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. An overexpression of wild-type GPI-anchored ceruloplasmin in Chinese hamster ovary cells led to the formation of aggresome-like inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with gamma-tubulin and a disruption of microtubules using nocodazole blocked the formation of such inclusions. Aceruloplasminemia-linked mutant proteins failed to form such inclusions even after treatment with proteasomal inhibitors. An immunofluorescent analysis indicated that the mutant proteins were thus retained in the endoplasmic reticulum (ER), whereas the transfected cells showed a decreased viability. The expression of glucose-regulated protein 78 that is one of the ER stress sensor proteins, and the activity of glucose-regulated protein 78 promoter was upregulated in the cells transfected with the mutants. These findings indicated that when the overexpressed cytoplasmic wild-type ceruloplasmin was not subjected to degradation by the proteasome-ubiquitin system, then the wild-type protein was transported along the microtubules, thus forming inclusions at the microtubule organizing center, whereas the mutant ceruloplasmin failed to form any such inclusions, because the mutant protein might not have been translocated across the ER into the cytoplasm. Therefore, the mutant protein was considered to have accumulated in the ER thus leading to the ER stress, which resulted in cell death.
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PMID:Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia. 1677 87

FgFtr1 and FgFtr2 are putative iron permeases, and FgFet1 and FgFet2 are putative ferroxidases of Fusarium graminearum. They have high homologies with iron permease ScFtr1 and ferroxidase ScFet3 of Saccharomyces cerevisiae at the amino acid level. The genes encoding iron permease and ferroxidase were localized to the same chromosome in the manner of FgFtr1/FgFet1 and FgFtr2/FgFet2. The GFP (green fluorescent protein)-fused versions of FgFtr1 and FgFtr2 showed normal functions when compared with FgFtr1 and FgFtr2 in an S. cerevisiae system, and the cellular localizations of FgFtr1 and FgFtr2 in S. cerevisiae depended on the expression of their putative ferroxidase partners FgFet1 and FgFet2 respectively. Although FgFtr1 was found on the plasma membrane when FgFet1 and FgFtr1 were co-transformed in S. cerevisiae, most of the FgFtr1 was found in the endoplasmic reticulum compartment when co-expressed with FgFet2. Furthermore, FgFtr2 was found on the vacuolar membrane when FgFet2 was co-expressed. From the two-hybrid analysis, we confirmed the interaction of FgFtr1 and FgFet1, and the same result was found between FgFtr2 and FgFet2. Iron-uptake activity also depended on the existence of the respective partner. Finally, the FgFtr1 and FgFtr2 were found on the plasma and vacuolar membrane respectively, in F. graminearum. Taken together, these results strongly suggest that FgFtr1 and FgFtr2 from F. graminearum encode the iron permeases of the plasma membrane and vacuolar membrane respectively, and require their specific ferroxidases to carry out normal function. Furthermore, the present study suggests that the reductive iron-uptake system is conserved from yeast to filamentous fungi.
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PMID:Physical and functional interaction of FgFtr1-FgFet1 and FgFtr2-FgFet2 is required for iron uptake in Fusarium graminearum. 1765 22

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients.
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PMID:Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin. 2065 81

We report a Japanese woman diagnosed as aceruloplasminemia showing characteristic symptoms. Mutational analysis of CP gene revealed a novel homozygous mutation in exon 18, resulting in prematurely truncated W1017X protein. In vitro study showed that W1017X mutant ceruloplasmin was deficient in endoplasmic reticulum to Golgi trafficking and was not secreted to medium. It has been reported that the presence of both the G (FLI/LI) GP domain and the 881th cysteine residue was sufficient for secretion. Thus, our report on this novel mutant indicates the previously unreported importance of carboxy-terminus residues in the secretion pathway.
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PMID:Aceruloplasminemia in a Japanese woman with a novel mutation of CP gene: clinical presentations and analysis of genetic and molecular pathogenesis. 2082 64


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