Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of iron is critical for maintaining homeostasis in the tsetse fly (Diptera: Glossinidae), in which both adult sexes are strict blood feeders. We have characterized the cDNAs for two putative iron-binding proteins (IBPs) involved in transport and storage; transferrin (GmmTsf1) and ferritin from Glossina morsitans morsitans. GmmTsf1 transcripts are detected in the female fat body and in adult reproductive tissues, and only in the adult developmental stage in a bloodmeal independent manner. In contrast, the ferritin heavy chain (GmmFer1HCH) and light chain (GmmFer2LCH) transcripts are expressed ubiquitously, suggesting a more general role for these proteins in iron transport and storage. Protein domain predictions for each IBP suggest both the conservation and loss of several motifs present in their vertebrate homologues. In concert with many other described insect transferrins (Tfs), putative secreted GmmTsf1 maintains 3 of the 5 residues necessary for iron-binding in the N-terminal lobe, but exhibits a loss of this iron-binding ability in the C-terminal lobe as well as a loss of large sequence blocks. Both putative GmmFer1HCH and GmmFer2LCH proteins have signal peptides, similar to other insect ferritins. GmmFer2LCH has lost the 5'UTR iron-responsive element (IRE) and, thus, translation is no longer regulated by cellular iron levels. On the other hand, GmmFer1HCH maintains both the conserved ferroxidase center and the 5'UTR IRE; however, transcript variants suggest a more extensive regulatory mechanism for this subunit.
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PMID:Molecular characterization of iron binding proteins from Glossina morsitans morsitans (Diptera: Glossinidae). 1709 67

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin.
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PMID:The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. 1716 53

Animal cytosolic ACO (aconitase) and bacteria ACO are able to switch to RNA-binding proteins [IRPs (iron-regulatory proteins)], thereby playing a key role in the regulation of iron homoeostasis. In the model plant Arabidopsis thaliana, we have identified three IRP1 homologues, named ACO1-3. To determine whether or not they may encode functional IRP proteins and regulate iron homoeostasis in plants, we have isolated loss-of-function mutants in the three genes. The aco1-1 and aco3-1 mutants show a clear decrease in cytosolic ACO activity. However, none of the mutants is affected in respect of the accumulation of the ferritin transcript or protein in response to iron excess. cis-acting elements potentially able to bind to the IRP have been searched for in silico in the Arabidopsis genome. They appear to be very rare sequences, found in the 5'-UTR (5'-untranslated region) or 3'-UTR of a few genes unrelated to iron metabolism. They are therefore unlikely to play a functional role in the regulation of iron homoeostasis. Taken together, our results demonstrate that, in plants, the cytosolic ACO is not converted into an IRP and does not regulate iron homoeostasis. In contrast with animals, the RNA binding activity of plant ACO, if any, would be more likely to be attributable to a structural element, rather than to a canonical sequence.
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PMID:The iron-responsive element (IRE)/iron-regulatory protein 1 (IRP1)-cytosolic aconitase iron-regulatory switch does not operate in plants. 1743 6

Ferritin plays a key role in cellular iron metabolism, which includes iron storage and detoxification. From disk abalone, Haliotis discus discus, the cDNA that encodes the two ferritin subunits abalone ferritin subunit 1 (Abf1) and abalone ferritin subunit 2 (Abf2) were cloned. The complete cDNA coding sequences for Abf1 and Abf2 contained 621 and 549 bp, encoding for 207 and 183 amino acid residues, respectively. The H. discus discus Abf2 subunit contained a highly conserved motif for the ferroxidase center, which consists of seven residues of a typical vertebrate heavy-chain ferritin with a typical stem-loop structure. Abf2 mRNA contains a 27 bp iron-responsive element (IRE) in the 5'UTR position. This IRE exhibited 96% similarity with pearl and Pacific oyster and 67% similarity with human H type IREs. However, the Abf1 subunit had neither ferroxidase center residues nor the IRE motif sequence; instead, it contained iron-binding region signature 2 (IBRS) residues. Recombinant Abf1 and Abf2 proteins were purified and the respective sizes were about 24 and 21 kDa. Abf1 and Abf2 exhibited iron-chelating activity 44.2% and 22.0%, respectively, at protein concentration of 6 microg/ml. Analysis of tissue-specific expression by RT-PCR revealed that Abf1 and Abf2 ferritin mRNAs were expressed in various abalone tissues, such as gill, mantle, gonad, foot and digestive tract in a wide distribution profile, but Abf2 expression was more prominent than Abf1.
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PMID:Two ferritin subunits from disk abalone (Haliotis discus discus): cloning, characterization and expression analysis. 1744 91

Iron closely regulates the expression of the Alzheimer's Amyloid Precursor Protein (APP) gene at the level of message translation by a pathway similar to iron control of the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5' untranslated regions (5'UTRs). Using transfection based assays in SH-SY5Y neuroblastoma cells we tested the relative efficiency by which iron, copper and zinc up-regulate IRE activity in the APP 5'UTR. Desferrioxamine (high affinity Fe3+ chelator), (ii) clioquinol (low affinity Fe/Cu/Zn chelator), (iii) piperazine-1 (oral Fe chelator), (iv) VK-28 (oral Fe chelator), were tested for their relative modulation of APP 5' UTR directed translation of a luciferase reporter gene. Iron chelation based therapeutic strategies for slowing the progression of Alzheimer's disease (and other neurological disorders that manifest iron imbalance) are discussed with regard to the relative neural toxic action of each chelator in SH-SY5Y cells and in H4 glioblastoma cells.
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PMID:Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5'untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator. 1744 34

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case-control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3'UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63.2 % of active TB compared with 6.8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.
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PMID:Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population. 1746 92

Cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme levels are elevated by the expression of the heavy chain ferritin (H ferritin) cDNA in cultured cells without corresponding changes in mRNA levels, resulting in enhanced folate-dependent de novo thymidylate biosynthesis and impaired homocysteine remethylation. In this study, the mechanism whereby H ferritin regulates cSHMT expression was determined. cSHMT translation is shown to be regulated by an H ferritin-responsive internal ribosome entry site (IRES) located within the cSHMT mRNA 5'-untranslated region (5'-UTR). The cSHMT 5'-UTR exhibited IRES activity during in vitro translation of bicistronic mRNA templates, and in MCF-7 and HeLa cells transfected with bicistronic mRNAs. IRES activity was depressed in H ferritin-deficient mouse embryonic fibroblasts and elevated in cells expressing the H ferritin cDNA. H ferritin was shown to interact with the mRNA-binding protein CUGBP1, a protein known to interact with the alpha and beta subunits of eukaryotic initiation factor eIF2. Small interference RNA-mediated depletion of CUGBP1 decreased IRES activity from bicistronic templates that included the cSHMT 3'-UTR in the bicistronic construct. The identification of this H ferritin-responsive IRES represents a mechanism that accounts for previous observations that H ferritin regulates folate metabolism.
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PMID:A ferritin-responsive internal ribosome entry site regulates folate metabolism. 1770 48

Ferritin plays a key role in cellular iron metabolism including iron storage and detoxification, which has been identified in a wide range of organisms including bacteria, fungi, plants and animals. However, little information is available regarding ferritin in the protochordates to date. Here we demonstrate the presence of a ferritin gene homolog, BbFRT, in amphioxus Branchiostoma belcheri. Analysis of the BbFRT 5'-UTR indicated the existence of a putative iron-responsive element (IRE) with a predicated stem-loop structure. BbFRT encoded a deduced protein of 172 amino acids with the conserved motif for ferroxidase center typical of heavy chains of vertebrate ferritins. Sequence comparison showed that BbFRT shared more identity to H-chains (68%) of vertebrate ferritins than to the L-chains (46-51%). Both in situ hybridization histochemistry and immunohistochemical staining revealed that BbFRT was ubiquitously expressed in B. belcheri. In addition, BbFRT expression was up-regulated by 1.6-fold and 1.5-fold, respectively, following exposure to LPS at both transcriptional and translational levels. Similarly, exposure to iron resulted in about 1.6-fold increase in BbFRT in the humoral fluids. These suggest that BbFRT seems a protein with a dual function functioning in both immune response and iron metabolism.
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PMID:Identification and expression of a ferritin homolog in amphioxus Branchiostoma belcheri: evidence for its dual role in immune response and iron metabolism. 1845 69

Transferrin and ferritin are iron-binding proteins involved in transport and storage of iron as part of iron metabolism. Here, we describe the cDNA cloning and characterization of transferrin (Bi-Tf) and the ferritin heavy chain subunit (Bi-FerHCH), from the bumblebee Bombus ignitus. Bi-Tf cDNA spans 2340 bp and encodes a protein of 706 amino acids and Bi-FerHCH cDNA spans 1393 bp and encodes a protein of 217 amino acids. Comparative analysis revealed that Bi-Tf appears to have residues comprising iron-binding sites in the N-terminal lobe, and Bi-FerHCH contains a 5'UTR iron-responsive element and seven conserved amino acid residues associated with a ferroxidase center. The Bi-Tf and Bi-FerHCH cDNAs were expressed as 79 kDa and 27 kDa polypeptides, respectively, in baculovirus-infected insect Sf9 cells. Northern blot analysis revealed that Bi-Tf exhibits fat body-specific expression and Bi-FerHCH shows ubiquitous expression. The expression profiles of the Bi-Tf and Bi-FerHCH in the fat body of B. ignitus worker bees revealed that Bi-Tf and Bi-FerHCH are differentially induced in a time-dependent manner in a single insect by wounding, bacterial challenge, and iron overload.
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PMID:Molecular characterization of iron binding proteins, transferrin and ferritin heavy chain subunit, from the bumblebee Bombus ignitus. 1882 42

The hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by juvenile-onset cataracts and elevated serum ferritin levels. It is caused by mutation in the iron response element (IRE) within the 5'UTR of L-ferritin gene. The mutation results in a loss of post-transcriptional negative feedback exerted by the interaction between iron regulatory proteins 1, 2 (IRP1 and IRP2) and IRE, which leads to uncontrolled expression of L-ferritin. In this paper, we describe the molecular pathogenesis of non-hereditary hyperferritinemia cataract syndrome (non-H-HCS) in a patient with typical HHCS ocular lens morphology and high ferritin levels without obvious family history. Initial sequencing of the full-length L-ferritin cloned from genomic DNA demonstrated a mutation (C33>T) in the IRE of the affected patient but not in her unaffected family members. The mutation (C/T heterozygote) was also detected in cDNA derived from her blood mononuclear cells. Structure-prediction-modeling indicates that this mutation would significantly alter the secondary structure of the IRE, resulting in a loss of the interaction between IRP and IRE. By using IRP1/IRP2-human IgG1 Fc fusion proteins, we established a novel in vitro report system (modified ELISA) to verify impaired IRE/IRP binding. Both the C33>U and A40G mutations (the first identified mutation for HHCS) showed a dramatically decreased binding to IRP1/IRP2 protein, compared to the normal IRE RNA. Surprisingly, a decrease in L-ferritin mRNA levels was observed in the affected patient compared to controls suggesting a mechanism of transcriptional negative feedback by high intracellular L-ferritin protein levels not described heretofore. Taken together, spontaneous mutation in the IRE of L-ferritin may cause non-H-HCS by the same mechanism as HHCS. In addition, under abnormal circumstances, the protein level of L-ferritin may be principally controlled by post-transcriptional regulation rather than the transcriptional regulation. The successful establishment of an ELISA report system provides an alternative method to evaluate precisely the interaction between protein and RNA.
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PMID:A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome. 1980 Feb 71


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