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)

It is well established that Fe and ceruloplasmin interact in animals and in in vitro models. However, Fe-mediated regulation of ceruloplasmin has never been investigated in humans. In an observational study, 53 pregnant women aged 19-39 yr (29.8 +/- 0.7 yr, mean +/- SEM) were recruited at the Aberdeen Antenatal Clinic, Aberdeen Maternity Hospital, UK. All requirements for local ethical committees were followed. Venous blood samples were taken from each woman at 34 wk gestation for measurement of Fe status and ceruloplasmin. Various parameters were used to test for Fe status. The most sensitive one appeared to be soluble transferrin receptor, which increased with parity. In the population studied, there was no relationship between hemoglobin or ferritin and serum ceruloplasmin. However, using soluble transferrin receptor (sTfR) levels, we were able to demonstrate an inverse linear relationship (r = 0.37, p = 0.021, n = 41) between Fe status and ceruloplasmin. Fe supplementation, number of previous pregnancies, and smoking habits did not affect this relationship. Our data support in vitro results showing regulation of ceruloplasmin by Fe and also suggest that the interactions between Fe and ceruloplasmin should be considered when Fe supplementation is given.
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PMID:Interrelations between ceruloplasmin and Fe status during human pregnancy. 1505 95

Iron, the major trace element in the body, is an essential component of many proteins and enzymes. As low-molecular-weight iron is potentially toxic to cells, higher organisms express a number of proteins for the transport and storage of iron. We review our current understanding of the intestinal absorption of iron in the light of recently identified membrane proteins, namely the ferrric reductase, Dcytb, the two iron(II) transport proteins, DMT1 and ferroportin/Ireg1, and hephaestin, the membrane-bound homologue of the ferroxidase ceruloplasmin. Two types of mammalian transferrin receptor, TfR1 and TfR2, are now known to exist. The structure of TfR1 and its role in the process of receptor-mediated cellular uptake of iron are presented together with structural information on the iron storage protein ferritin. Mechanisms for the regulation of levels of TfR1 and ferritin, as well as other proteins involved in iron homeostasis, are discussed. Our current knowledge and understanding of the structure of members of the transferrin family of iron-binding proteins and the nature of the iron-binding centres in transferrins is presented, together with information on the processes of iron-uptake and iron-release by transferrin and a summary of the elements that have been found to bind to transferrins.
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PMID:Structure/function overview of proteins involved in iron storage and transport. 1630 65

Iron that is not specifically chaperoned through its essential functional pathways is damaging to biological systems, in major part by catalyzing the production of reactive oxygen species. Iron serves in several essential roles in the mitochondrion, as an essential cofactor for certain enzymes of electron transport, and through its involvement in the assembly of iron-sulfur clusters and iron-porphyrin (heme) complexes, both processes occurring in the mitochondrion. Therefore, there are mechanisms that deliver iron specifically to mitochondria, although these are not well understood. Under normal circumstances the mitochondrion has levels of stored iron that are higher than other organelles, though lower than in cytosol, while in some disorders of iron metabolism, mitochondrial iron levels exceed those in the cytosol. Under these circumstances of excess iron, protective mechanisms are overwhelmed and mitochondrial damage ensues. This may take the form of acute oxidative stress with structural damage and functional impairment, but also may result in long-term damage to the mitochondrial genome. This review discusses the evidence that mitochondria do indeed accumulate iron in several genetic disorders, and are a direct target for iron toxicity when it is present in excess. We then consider two classes of genetic disorders involving iron and the mitochondrion. The first include defects in genes directly regulating mitochondrial iron metabolism that lead to Friedreich's ataxia and the various sideroblastic anemias, with excessive mitochondrial iron accumulation. Under the second class, we discuss various primary hemochromatoses that lead to direct mitochondrial damage, with reference to mutations in genes encoding HFE, hepcidin, hemojuvelin, transferrin receptor-2, ferroportin, transferrin, and ceruloplasmin.
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PMID:Mitochondrial involvement in genetically determined transition metal toxicity I. Iron toxicity. 1679 9

Brain iron uptake is regulated by the expression of transferrin receptor 1 in endothelial cells of the blood-brain barrier. Transferrin-bound iron in the systemic circulation is endocytosed by brain endothelial cells, and elemental iron is released to brain interstitial fluid, likely by the iron exporter, ferroportin. Transferrin synthesized by oligodendrocytes in the brain binds much of the iron that traverses the blood-brain barrier after oxidation of the iron, most likely by a glycophosphosinositide-linked ceruloplasmin found in astrocytic foot processes that ensheathe brain endothelial cells. Neurons acquire iron from diferric transferrin, but it is less clear how glial cells acquire iron. In aging mammals, iron accumulates in the basal ganglia, and iron accumulation is believed to contribute to neurodegenerative diseases, including Parkinson and Alzheimer disease. Here we consider the possibility that iron accumulations, which are often thought to facilitate free radical generation and oxidative damage, may contain insoluble iron that is unavailable for cellular use, and the pathology associated with iron accumulations may result from functional iron deficiency in some diseases.
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PMID:Brain iron metabolism. 1710 52

Cu and Fe metabolism are known to be linked, but the interactions during pregnancy are less well studied. In the present study we used rats to examine the effect of Cu deficiency during pregnancy on Fe and Cu levels in maternal and fetal tissue and on the gene expression profile of proteins involved in Cu and Fe metabolism in the placenta. Rats were fed diets with different Cu contents before and during pregnancy. Samples were collected on day 21 of gestation. Cu levels, ceruloplasmin activity and serum Fe all decreased in maternal serum of Cu-deficient animals. Maternal liver Fe inversely correlated with liver Cu. Placental Cu levels decreased with no change in Fe. Fe and Cu levels both decreased in the fetal liver. The drop in maternal liver Cu was significantly correlated with a decrease in organ weight of fetal liver, lung and kidney. No changes were observed in mRNA expression of Cu transporter 1, Menkes P-type Cu-ATPase 7A, Wilson P-type Cu-ATPase 7B, cytochrome-c oxidase, and Cu chaperone Atox1 in the placenta of Cu-deficient dams. Transferrin receptor 1 and the Fe-responsive element (IRE)-regulated divalent metal transporter 1 (DMT1) were up regulated; while ferroportin and non-IRE1-regulated DMT1 levels did not change. These data show that Cu deficiency during pregnancy not only has a direct effect on Fe levels but also regulates the expression of Fe transporters. The pattern closely mirrors that seen in Fe deficiency, suggesting that the changes are a consequence of the decrease in serum Fe, implying that the developing fetus not only suffers from Cu, but also from Fe deficiency.
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PMID:Effect of dietary copper deficiency on iron metabolism in the pregnant rat. 1729 91

Iron-mediated injury plays an important role in a number of heart disorders. Studies on heart iron are therefore crucial for understanding the causes of excessive heart iron. Heart cells have the ability to accumulate transferrin-bound-iron via the transferrin receptor and non-transferrin-bound-iron probably via the L-type Ca2+ channel and the divalent metal transporter1. However, little is known about the mechanisms of iron export in the heart cells. Here, we investigated expression of iron exporters including ferroportin 1 (Fpn1), ceruloplasmin (CP) and hephaestin (Heph) and provided evidence for their existence in the heart. We demonstrated that iron has a significant effect on expression of Fpn1 and CP, but not Heph. Treatment of a high-iron diet induced a significant increase in Fpn1, a decrease in CP but no change in Heph mRNA and protein. The control of Fpn1 and CP protein expression by iron was parallel to that of their mRNA expression, suggesting a transcriptional regulation of Fpn1 and CP by iron. The existence of these proteins in the heart implies that they might have a role in heart iron homeostasis.
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PMID:Expression of ferroportin1, hephaestin and ceruloplasmin in rat heart. 1738 61

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels buildup with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich's ataxia, and panthothenate kinase-associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age-matched controls. Over the past 10 years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter-1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron-regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron-induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential.
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PMID:Iron homeostasis and toxicity in retinal degeneration. 1792 Oct 41

Iron accumulation is associated with age-related neurodegenerations and may contribute to age-related increased susceptibility of neurons to damage. We compared young and old rodent retinas to assess iron homeostasis during normal aging and the effects of increased iron on the susceptibility of retinal neurons to degeneration. Retinal iron was significantly increased with age. Quantitative RT-PCR showed that transferrin and ferritin genes were upregulated in the aged retina. At the protein level, we found decreased transferrin, and increased transferrin receptor, ferritin, ferroportin, and ceruloplasmin in the aged retina. These results support an increased steady state of iron with age in the retina. We tested susceptibility of retinal neurons with increased intracellular iron to damage in vitro. Exposure of RGC-5 cells to increased iron potentiated the neurotoxicity induced by paraquat, glutamate, and TNFalpha. Our results demonstrate that iron homeostasis in the retina is altered with age and suggest that iron accumulation, due to altered levels of iron-regulatory proteins in the aged retina, could be a susceptibility factor in age-related retinal diseases.
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PMID:Changes in iron-regulatory proteins in the aged rodent neural retina. 1830 29

Eighty-nine pregnant women, including 62 pregnant females with pyelonephritis, were examined. After bacteriophage treatment for pyelonephritis, there was an increase in the content of iron, a decrease in the level of soluble transferrin receptor without iron therapy, suggesting iron redistribution in pregnant woman. The blood levels of copper, ceruloplasmin, and transferrin in pregnant women with pyelonephritis point to antioxidative defense activation in both healthy pregnant women and pregnant females with pyelonephritis. The serum concentration of ceruloplasmin is of importance for prognosis and evaluation of ceruloplasmin in pregnant women. The higher content of ceruloplasmin in pregnancy is indicative of the involvement of protective mechanisms from autoaggression.
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PMID:[Effect of bacteriophage on the serum level of iron and copper in pregnant women with pyelonephritis]. 1872 Jul 32

This paper investigates the extent to which Cu loading influences Fe levels in HepG2 cells and the effect on proteins regulated by Fe status. Cu supplementation increased Cu content 3-fold, concomitant with a decrease in cellular Fe levels. Intracellular levels of both transferrin (Tf) and ceruloplasmin (Cp) protein rose in parallel with increased secretion into the culture media. There was no increase in mRNA levels for either protein. Rather, our data suggested increased translation of the mRNA. The increase was not reflected in total protein synthesis, which actually decreased. The effect was not a generalised stress or cell damage response, since heat shock protein 70 levels and lactate dehydrogenase secretion were not significantly altered. To test whether the Cu effect could be acting though the decrease in Fe levels, we measured transferrin receptor (TfR) levels using (125)I labeled Tf and mRNA analysis. Neither protein nor mRNA levels were changed. Neither was the level of ferroportin mRNA. As a positive control, Fe chelation increased Tf and Cp secretion significantly, and TfR mRNA levels rose 2-fold. We excluded the possibility that the increased Cp or Tf could provide the required substrate to stimulate Fe efflux, and instead demonstrate that Cu can substitute for Fe in the iron regulatory protein - iron responsive element regulation mechanism.
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PMID:Cu loading alters expression of non-IRE regulated, but not IRE regulated, Fe dependent proteins in HepG2 cells. 1923 37


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