UNIPROT:P02794 - FACTA Search

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

Query: UNIPROT:P02794 (ferritin)
17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 60-year-old man, although treated with antibiotics, suffered from a severe pyrexial illness of unknown origin, weight loss and intermittent abdominal pain. There was no history of diarrhea or common infections. Computed tomography and ultrasound imaging showed uncharacteristic multiple small lesions of the entire liver parenchyma. These lesions were histologically pyogenic abscesses. In addition, an unexpected, pronounced accumulation of iron pigment in hepatocytes and second degree fibrotic changes of the liver were detected. Serum iron and serum transferrin were low, but serum ferritin concentration and transferrin saturation were increased to the maximum. The demonstration of the cysteine-282-tyrosine mutation confirmed underlying primary hemochromatosis. Bacteriological cultures of the abscess material yielded Yersinia enterocolitica serotype O:3, while stool and blood cultures were negative. Antibiotic therapy with piperacillin/tazobactam and tobramycin was successful within a few days. A repeat CT scan and ultrasound imaging demonstrated complete regression of the pathologic liver morphology. The patient was discharged and treated with an orally administered fluoroquinolone for an additional 6 months. After this time the patient had no morphological residues of the infection except one enlarged lymph node near the portal vein but still was so weak that he was unable to work again. In conclusion, severe septic forms of yersiniosis are mainly found in patients with iron overload, due to a handicapped iron metabolism of the Yersinia bacteria. Mortality is high despite treatment.
...
PMID:Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis. 1125 17

Hereditary hemochromatosis (hh, type 1 hemochromatosis) is an autosomal recessive trait characterized by hyperabsorption of dietary iron. The disease trait occurs in approximately five per thousand Caucasians of northern European descent. The causative gene, designated HFE, was isolated and characterized in 1996; most individuals with hh are homozygous for a mutation resulting in a change from cysteine to tyrosine at residue 282 of the HFE protein (C282Y). Wild-type HFE protein binds to the transferrin receptor, and by an undefined mechanism the enterocyte is "programmed" to absorb an amount of dietary iron precisely matched to the body's needs. The C282Y mutant protein is not expressed on the cell surface and does not bind to the transferrin receptor; the result is an enterocyte programmed to absorb slightly more iron than required. Most individuals with hh display a common laboratory phenotype, an elevated transferrin saturation. Iron stores in excess of normal eventually occur in most men and some women. The prevalence of organ damage due to iron overload, however, remains a controversial issue. Published estimates range from less than 1% to "nearly all." The main reason for this discrepancy has been ascertainment bias. Retrospective studies have been biased in favor of individuals with morbid complications of hh, whereas screening studies of groups such as blood donors generally include only healthy subjects. We focus here on a review of studies that have attempted to avoid ascertainment bias. If biopsy-proven hepatic fibrosis and/or cirrhosis is employed as the single criterion for disease-related morbidity, clinical penetrance of hh occurs in 4% to 25% of homozygotes. This range, although narrower than in biased studies, is still wide and requires clarification. A large-scale population-based study has been sponsored by the National Institutes of Health to address this issue. Until results become available, the pragmatic approach is to continue to screen for hemochromatosis in the primary care setting and to maintain serum ferritin values at approximately 100 micro g/L or lower with phlebotomy therapy.
...
PMID:Hereditary hemochromatosis. 1238 98

Rheumatoid arthritis is an inflammatory joint and systemic disease believed to be of autoimmune origin. Predisposing factors also include genetic factors, such as the presence of alleles HLA-DRB1 *04, (HLA-DRB1 *0401, *0404, *0405 and *0408) and, in other ethnic groups, of subtypes DRB1 *0101, *0102 and DRB1 *1001. These genetic factors are believed to raise the risk of developing the disease. In rheumatoid arthritis, as in other chronic inflammatory diseases, iron metabolism dysfunction has been observed and attributed to inflammation. In hereditary hemochromatosis, tissue sideropexia is associated with a peculiar form of arthropathy. C282Y is a point mutation involving the replacement of a cysteine with a tyrosine at position 282 of the HFE protein. When found in homozygosis, there is a close association with hereditary hemochromatosis, accounting for one of the causes of iron metabolism dysfunction observed in this disease. The aim of this study was to compare the frequency of C282Y in patients with rheumatoid arthritis with that in patients with different forms of spondylarthritis and to correlate these findings with iron metabolism parameters. In the group of patients with rheumatoid arthritis, 2/24 (8.34%) were found to be positive for the C282Y mutation in the case of heterozygosis compared with 3/24 (12.5%) of patients with spondylarthritis. In patients with the C282Y mutation, ferritin levels were significantly higher than those in controls; conversely, serum iron levels were higher in patients with spondylarthritis. Serum transferrin levels, although slightly higher in rheumatoid arthritis patients, showed no statistically significant differences.
...
PMID:Prevalence of C282Y mutation in patients with rheumatoid arthritis and spondylarthritis. 1263 63

In the goodeid placental analogue, trophotaeniae provide extraembryonic gut-derived exchange surfaces. Ameca splendens embryos possess endocytosing trophotaeniae that are capable of absorbing a dazzling array of proteinaceous substances. The iron core protein, native ferritin (NF), and several radioiodinated proteinaceous substances were used to study ligand and binding site pathways in the trophotaenial absorptive cells (TACs). Time sequence analysis of NF trafficking indicated an exclusively lysosomal pathway. Binding to TACs of NF was completely inhibitable by proteins containing multiple lysine residues such as apoferritin, bovine serum albumin (BSA), human transferrin (HTf), fetuin, hemoglobin, myoglobin, cytochrome c, ubiquitin, parvalbumin as well as the random copolymers, poly(Glu,Lys,Tyr)6:3:1 and poly(D-Glu,D-Lys)6:4. Peptide hormones and pepsin that contains only one lysine residue did not produce inhibitory effects. Radiolabels such as (125)I-BSA, (125)I-HTf and (125)I-poly(Glu,Lys,Tyr) bound to trophotaeniae in a specific saturable manner. Any two proteins were shown to hinder one another in getting hold of a binding site. Concentration-dependent (125)I-BSA binding and Scatchard analysis of the data revealed both low- and medium-affinity binding with apparent dissociation constants, K(d)s, of 3.4 x 10(-5) M and 2 x 10(-7) M, respectively. Binding of NF and radioiodinated proteins was inhibited in the presence of a large excess of L-Lys, D-Lys, and several dipeptides containing Lys. Both Ca(2+)-depletion and low pH dramatically reduced the TACs' capacity to bind proteins. The effects of acidotropic agents included a reversible loss of surface protein binding sites, tremendous vacuolation, and the arrest of lysosomal degradation. Collectively, present results demonstrate that TACs bind and absorb multiple proteinaceous substances through a mechanism satisfying the criteria of receptor-mediated endocytosis. It is concluded that scavenger protein binding sites are used to ingest proteins for lysosomal degradation, helping to meet the embryos' amino acid requirement.
...
PMID:Scavenger receptors facilitate protein transport in the trophotaenial placenta of the goodeid fish, Ameca splendens (Teleostei: Atheriniformes). 1297 8

Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level. Because IRP-1 is a sensitive target protein for nitric oxide (NO), we investigated whether this protein is nitrated in inflammatory macrophages and whether this post-transcriptional modification changes its activities. RAW 264.7 macrophages were first stimulated with interferon-gamma and lipopolysaccharide (IFN-gamma/LPS) and then triggered by phorbol 12-myristate 13-acetate (PMA) in order to promote co-generation of NO* and O*2-.. IRP-1 was isolated by immunoprecipitation and analyzed for protein-bound nitrotyrosine by Western blotting. We show that nitration of endogenous IRP-1 in NO-producing macrophages boosted to produce O*2- was accompanied by aconitase inhibition and impairment of its capacity to bind the iron-responsive element (IRE) of ferritin mRNA. Lost IRE-binding activity was not recovered by exposure of IRP-1 to 2% 2-mercaptoethanol and was not due to protein degradation. Inclusion of cis-aconitate with cell extract to stabilize the [4Fe-4S] cluster of holo-IRP-1 rendered protein insensitive to nitration by peroxynitrite, suggesting that loss of [Fe-S] cluster and subsequent change of conformation are prerequisites for tyrosine nitration. IRP-1 nitration was strongly reduced when IFN-gamma/LPS/PMA-stimulated cells were incubated with myeloperoxidase inhibitors, which points to the contribution of the nitrite/H2O2/peroxidase pathway to IRP-1 nitration in vivo. Interestingly, under these conditions, IRP-1 recovered full IRE binding as assessed by treatment with 2% 2-mercaptoethanol. Peroxidase-mediated nitration of critical tyrosine residues, by holding IRP-1 in an inactive state, may constitute, in activated macrophages, a self-protecting mechanism against iron-induced toxicity.
...
PMID:Endogenous nitration of iron regulatory protein-1 (IRP-1) in nitric oxide-producing murine macrophages: further insight into the mechanism of nitration in vivo and its impact on IRP-1 functions. 1525 60

The R2 subunit of Escherichia coli ribonucleotide reductase contains a diiron site that reacts with O(2) to produce a tyrosine radical (Y122.). In wild-type R2 (R2-wt), the first observable reaction intermediate is a high-valent [Fe(III)-Fe(IV)] state called compound X, but in related diiron proteins such as methane monooxygenase, Delta(9)-desaturase, and ferritin, peroxodiiron(III) complexes have been characterized. Substitution of iron ligand D84 by E within the active site of R2 allows an intermediate (mu-1,2-peroxo)diiron species to accumulate. To investigate the possible involvement of a bridging peroxo species within the O(2) activation sequence of R2-wt, we have characterized the iron-nitrosyl species that form at the diiron sites in R2-wt, R2-D84E, and R2-W48F/D84E by using vibrational spectroscopy. Previous work has shown that the diiron center in R2-wt binds one NO per iron to form an antiferromagnetically coupled [(FeNO)(7)](2) center. In the wt and variant proteins, we also observe that both irons bind one NO to form a (FeNO)(7) dimer where both Fe-N-O units share a common vibrational signature. In the wt protein, nu(Fe-NO), delta(Fe-N-O), and nu(N-O) bands are observed at 445, 434 and 1742 cm(-1), respectively, while in the variant proteins the nu(Fe-NO) and delta(Fe-N-O) bands are observed approximately 10 cm(-1) higher and the nu(N-O) approximately 10 cm(-1) lower at 1735 cm(-1). These results demonstrate that all three proteins accommodate fully symmetric [(FeNO)(7)](2) species with two identical Fe-N-O units. The formation of equivalent NO adducts in the wt and variant proteins strongly favors the formation of a symmetric bridging peroxo intermediate during the O(2) activation process in R2-wt.
...
PMID:Characterization of NO adducts of the diiron center in protein R2 of Escherichia coli ribonucleotide reductase and site-directed variants; implications for the O2 activation mechanism. 1531 37

Iron overload causes impaired function of tissues and organs due to the increased iron storage in them. Hereditary hemochromatosis is the most frequent hereditary metabolic disorder, with lethal outcome without treatment. The genetic disorder is a mutation on the short arm of the 6. chromosome, which resulted a cysteine-tyrosine substitution on the 282. amino acid position (C282Y). This mutation is less frequent in the non-Caucasian population, in opposition to the other reported mutation (H63D). The risk of the development of the disease is the highest in people who are C282Y homozygotes or C282Y/H63D compound heterozygotes. The prevalence of hemochromatosis is 1.5-5.9 per thousand. Liver disease/cirrhosis, diabetes mellitus and hyperpigmentation are the classic signs of the disease. Primer hepatocellular cancer occurs in 30% of patients with liver cirrhosis, that it is the most common cause of death among them. The diagnosis is based on the detection of iron overload (transferrin saturation, serum ferritin level, iron concentration of the liver tissue) and on the genetic examinations. Early diagnosis makes the causal therapy possible, which is the removal of the iron excess by phlebotomy. Furthermore, the early detection of iron overload allows of prevention of the development of the disease. Based in these facts population screening seems to be necessary and cost-effective, but further studies are required to determine the exact screening strategy.
...
PMID:[Iron storage disease]. 1555 8

The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth.
...
PMID:HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. 1604 95

Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83% of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein. HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease. Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. This review gives the background and a model as to possible mechanisms of how HFE could exert different effects on iron homeostasis in different cell types.
...
PMID:Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis. 1662 71

Polymer-based biomedical devices are growing increasingly sophisticated as compositions evolve toward copolymers and blends in order to satisfy complex design criteria. Such polymers afford opportunities for both micro- and macrophase separation at nano- and micro-length scales and raise questions concerning the role of heterogeneous surface morphology on protein adsorption. Adsorbed protein layers play a critical role in mediating the interaction of cells with polymer surfaces, and both understanding and controlling protein adsorption is assuming greater significance in the development of surfaces with enhanced physiological compatibility. Here we study the short-time adsorption of ferritin, a model protein highly resistant to denaturation and easily imaged in the transmission electron microscope (TEM), onto a phase-separated homopolymer blend of polycaprolactone (PCL) and a polycarbonate derived from desaminotyrosyl-tyrosine dodecyl ester (PDTD). At physiological pH, ferritin selectively adsorbs onto the PDTD phase at a surface density approximately three times greater than that on the PCL phase. By decreasing the pH below ferritin's isoelectric point so its average charge becomes positive, the selective adsorption disappears and the surface density of adsorbed ferritin becomes independent of the phase separation. We attribute the selectivity to the electrostatic repulsion between ferritin and hydrolytically charged PCL, both of which will have a net negative charge at physiological pH. To perform these experiments, we solvent-cast ultrathin polymer films onto dissolvable salt substrates, and we characterize the morphology by TEM imaging and quantitative spatially resolved electron energy-loss spectroscopy (EELS). We find that the film morphology depends strongly on such processing-related variables as the solvent evaporation rate and the nature of the surface in contact with the polymer film during casting. The adsorption of ferritin depends on whether the film is phase-separated as well as to which surface of the film the protein solution is exposed, and these findings suggest that seemingly small variations in polymer processing that influence both the bulk and surface morphology can have a profound effect on the short-time protein adsorption.
...
PMID:Selective protein adsorption on a phase-separated solvent-cast polymer blend. 1680 Jun 88

<< Previous 1 2 3 4 5 6 Next >>