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 iron storage molecule, ferritin, consists of an iron core surrounded by a shell of 24 protein subunits, which, in mammals, are of two types, H and L. Prior to storage of iron as a hydrous ferric oxide within the protein shell, Fe(II) is catalytically oxidized at dinuclear centers within H chains. When 48 Fe(II) atoms/molecule were added to 1 microM recombinant human H chain apoferritin (apo-HuHF), in 0.1 M Mes (pH 6.5), oxidation was 80% complete within about 0.2 s while 99% of the Fe(II) was oxidized within 10 s. A broad visible absorption band (400-800 nm, with a maximum at 650 nm) appeared during the fast phase of Fe(II) oxidation. It reached a plateau at 0.2-0.3 s and then declined while Fe(II) oxidation proceeded to completion and absorbance in the near-UV (300-400 nm) increased. The transient visible species was not observed when Tyr-34 was replaced by phenylalanine or when other conserved amino acids at the ferroxidase centers were substituted by residues which are unable to bind iron or which alter the charge balance. When a second increment of 48 iron atoms was added, 10 min after the first, the visible absorbance was absent and the rate of oxidation slower. Restoration of full oxidative activity took over 24 h. The data indicate that the fast oxidation of Fe(II) by apo-HuHF and the transient visible absorbance associated with it are due to Fe(II) oxidation at the ferroxidase centers.
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PMID:Iron(II) oxidation by H chain ferritin: evidence from site-directed mutagenesis that a transient blue species is formed at the dinuclear iron center. 757 35

To examine RNA/protein synthesis of neutrophils and related dynamic changes during the inflammatory process, we investigated mRNA expressions in neutrophils, by RNA blot hybridization analyses using 12 different rabbit gene probes. We first selected five candidate genes encoding inflammation-related proteins, i.e. tumor necrosis factor (TNF-alpha) IL-1 alpha, IL-1 beta, neutrophil activating peptide-1/IL-8 (NAP-1/IL-8) and monocyte chemoattractant protein (MCP)-1. We further selected several genes on basis of the results from gene subtraction between cDNA libraries from neutrophils at an early (5 h) and at a late (24 h) stage of casein-induced acute peritonitis in rabbits, i.e. immune activation gene-2 (Act-2), migration inhibitory factor-related protein-8 (MRP-8), MRP-14, gamma-actin, and formyl-methionyl-leucyl-phenylalanine receptor (fMLP-R), and ferritin light (L) chain. In addition to these genes we used ferritin heavy (H) chain gene, another component of the ferritin molecule. We examined mRNA expressions by cytoplasmic slot blot analysis of the above 12 genes in neutrophils obtained from blood and from various stages of casein-induced inflammation in rabbits. The observed patterns of mRNA expression kinetics were classified into three. Pattern 1: mRNAs of MRP-8, MRP-14, and gamma-actin were constitutively expressed in blood neutrophils, and increased rapidly after emigration into inflammatory sites. Pattern 2: mRNAs of IL-1 beta, NAP-1/IL-8, Act-2, and fMLP-R were undetectable in blood neutrophils, and were induced rapidly after the onset of inflammation. Pattern 3 mRNAs of ferritin L and H chain were induced slowly, and increased with progression of the inflammatory process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dynamic changes in mRNA expression of neutrophils during the course of acute inflammation in rabbits. 814 23

We showed previously that the abundance of serum albumin mRNA is decreased in H4-II-E rat hepatoma cells limited for a single essential amino acid (phenylalanine, methionine, leucine, or tryptophan). To define the specificity of this phenomenon, we examined the effect of amino acid limitation on the abundance of mRNAs for 19 genes in the H4-II-E cells. These genes included six genes whose expression is either completely liver-specific or highly enriched in the liver compared with other tissues [albumin, transthyretin (TTR), transferrin, carbamyl phosphate synthetase-I, urate oxidase, class I alcohol dehydrogenase], as well as a number of ubiquitously expressed "housekeeping" genes. The results indicated that the 19 genes could be divided into three classes based on their response to amino acid limitation. Class I genes (the six liver-specific genes and alpha-tubulin) exhibit decreased expression in response to amino acid limitation. The expression of class II genes [beta 2-microglobulin, hypoxanthine-guanine phosphoribosyl transferase (HPRT), H-ferritin, ubiquitin (UbB), insulin-like growth factor binding protein-4, HNF-1 alpha] is not significantly affected by amino acid limitation. Class III genes [gadd153, beta-actin, ubiquitin (UbC), phosphoglycerate kinase-1, C/EBP alpha, C/EBP beta] exhibit increased expression in response to amino acid limitation. Thus, specific inductive as well as repressive effects on gene expression are quite common in amino acid-limited cells. The observation that all six genes whose expression is liver-specific exhibited decreased expression in amino acid-limited cells suggests a common mode of regulation of these genes by amino acid availability. The strong induction by amino acid limitation of the C/EBP inhibitor gadd153 is of interest in this regard, as increased levels of gadd153 could interfere with C/EBP, which is required for high expression of most liver-specific genes. To investigate further the molecular mechanism for the decrease in albumin mRNA abundance, albumin nuclear transcript levels were quantified in control and tryptophan-limited cells. Tryptophan limitation caused a decrease in albumin nuclear transcript abundance, and this decrease preceded the decrease in albumin mRNA, suggesting that the decrease in albumin mRNA was caused at least partly by a decrease in albumin gene transcription. Additional experiments with actinomycin D indicated that albumin mRNA was also destabilized in the tryptophan-limited cells. Thus, the overall results indicate that the decrease in albumin mRNA in the tryptophan-limited cells is caused by a specific decrease in albumin nuclear transcript abundance and destabilization of albumin mRNA.
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PMID:Effect of amino acid limitation on the expression of 19 genes in rat hepatoma cells. 818 73

Iron (Fe) status and Fe supplementation were assessed in 20 children with phenylketonuria (PKU) through dietary intake and through measurements of ferritin, hematocrit, hemoglobin, mean cellular hemoglobin, mean cellular volume, serum Fe, total iron binding capacity, unbounded iron binding capacity, transferrin saturation and transferrin. Findings were compared to reference values and to data from age-matched controls. The prescribed phenylalanine-restricted diet supplied all the recommended nutrients. Dietary Fe was present in the diets, but its bioavailability is questionable as several laboratory results were not within accepted reference values. A ferrous sulphate supplement (5 mg elemental Fe/kg daily) was given for 120 days to a group of PKU children with lower Fe parameters, thus changing some of the parameters studied. Serum ferritin (p < 0.1), transferrin saturation and serum Fe (p < 0.05) increased after the treatment. The need for improved diagnosis of Fe status and determination of whether PKU children can benefit from therapeutic Fe is discussed.
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PMID:Iron status and iron supplementation in children with classical phenylketonuria. 826 69

A retrospective study of 53 patients with phenylketonuria (PKU), whose disease was managed with a low-phenylalanine diet, revealed a high incidence of iron depletion (as reflected by subnormal serum ferritin concentrations). Serum ferritin concentrations under 10 micrograms/l were found in one out of six infants aged 5-12 months. Concentrations under 16 micrograms/l were found in 16 of 22 children aged 1-3 years and in 11 of 25 children aged 4-12 years. Dietary iron, estimated from prescribed intakes of medical foods, exceeded the Canadian recommended nutrient intake, suggesting that low stores of iron may be secondary to reduced bioavailability and absorption of iron. These findings suggest that the current dietary management of PKU is associated with an increased risk for low iron stores. Investigators have reported an association in young children between iron-deficiency anaemia and both cognitive and motor disturbances. Children with PKU, already at risk of neurological damage because of phenylalanine neurotoxicity, may be at increased risk as a result of iron depletion. Serum ferritin as well as haemoglobin concentration should be monitored, along with plasma phenylalanine and tyrosine, to ensure optimum treatment of affected children.
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PMID:Low iron stores in infants and children with treated phenylketonuria: a population at risk for iron-deficiency anaemia and associated cognitive deficits. 844 22

The influence of copper (Cu) status on hepatic gene expression was examined by using the "messenger RNA differential display" technology. This method involves the distribution of mRNA in a two-dimensional array for the rapid identification and cloning of differentially expressed genes. Livers from male Sprague-Dawley rats that had been fed a Cu-deficient (CD) diet (9.4 micromol/kg) or a Cu-adequate (CA) diet (103.9 micromol/kg) for 6 wk were used to supply cytosolic RNA. Cytosolic RNA were reverse-transcribed in the presence of anchor primers and then amplified by polymerase chain reaction with anchor and arbitrary primer sets. The amplified cDNA were then resolved by denaturing polyacrylamide gel electrophoresis. Differences in mRNA expression between the CD and CA rats were identified. DNA fragments were cloned, sequenced and used as probes for Northern blot analysis to confirm that the identified genes were differentially expressed. The analysis of cDNA sequences by computer searches against DNA and protein databases revealed that one cDNA fragment, whose mRNA abundance was enhanced 1.2-fold by copper deficiency, is novel. Four other cDNA fragments were found to have substantial homology with rat ferritin mRNA; rat fetuin mRNA; rat mitochondrial 12S and 16S rRNA, phenylalanine-, valine- and leucine-tRNA genes; rat mitochondrial genes for 16S rRNA, tRNA-leucine and tRNA-valine; and their mRNA abundance was 0.6- to 0.8-fold higher in Cu-deficient rats. Five additional cDNAs detected by this method appeared to represent novel genes because they exhibited no substantial homology to recorded gene and protein sequences deposited in DNA and protein databases. These results demonstrate the usefulness of this technology in the detection of genes which were differentially expressed as a result of the deprivation of a single nutrient, dietary copper, in this research project.
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PMID:Enhanced expression of hepatic genes in copper-deficient rats detected by the messenger RNA differential display method. 868 38

Iron is thought to enter the ferritin cavity via the three-fold channel, which is lined in its narrowest part by the residues Asp-131 and Glu-134. We describe here variants of human ferritins with active and inactive ferroxidase centres having Asp-131 and Glu-134 substituted with Ala and Ala or with Ile and Phe respectively. The two types of substitution had similar effects on ferritin functionality: (i) they decreased the amount of iron incorporated from Fe(II) solutions and decreased ferroxidase activity by about 50%; (ii) they inhibited iron incorporation from Fe(III) citrate in the presence of ascorbate; (iii) they resulted in loss of Fe and Tb binding sites; and (iv) they resulted in a marked decrease in the inhibition of iron oxidation by Tb (but not by Zn). In addition, it was found that substitution with Ala of Cys-130 and His-118, both of which face the three-fold channel, decreased the capacity of H-ferritin to bind terbium and to incorporate iron from Fe(III) citrate in the presence of ascorbate. The results indicate that: (i) in three-fold channels are the major sites of iron transfer into the cavity of H- and L-ferritins; (ii) at least two metal binding sites are located on the channels which play an active role in capturing and transferring iron into the cavity; and (iii) the permeability of the channel is apparently not affected by the hydrophilicity of its narrowest part. In addition, it is proposed that iron incorporation from Fe(III) citrate complexes in the presence of ascorbate is a reliable, and possibly more physiological, approach to the study of ferritin functionality.
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PMID:Evidence that residues exposed on the three-fold channels have active roles in the mechanism of ferritin iron incorporation. 871 73

The effect of horse spleen ferritin (HFR) on the production of superoxide anion (O2.-) by equine blood monocytes was investigated. Preincubation of monocytes with HFR resulted in pronounced inhibition of O2.- production in response to phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP), and opsonized zymosan (OZ). The inhibitory effect of HFR upon stimulation of monocytes with PMA was both dose and time dependent. Maximum inhibition (90%) was observed after preincubation of monocytes with HFR (2 mg/ml) for 18 h before stimulation with PMA. ApoHFR at the same concentration showed only about one-third of the inhibitory effect of iron-saturated HFR. Various iron complexes, such as iron dextran, hemin, or ferric ammonium sulfate, had no significant effect on O2.- production by monocytes. Neither catalase (Cat) nor desferrioxamine (DFO) changed the inhibitory effect of HFR. These findings suggest that HFR may play an important role in inhibition of superoxide generation by equine monocytes. Although the mechanism of this inhibition remains unknown, the results obtained suggest that it is not due to ferritin-dependent oxidative inactivation of the NADPH-oxidase system in stimulated monocytes.
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PMID:Horse spleen ferritin inhibits superoxide production by equine blood monocytes in vitro. 872 16

Ferritin is a protein of 24 subunits which assemble into a shell with 432 point symmetry. It can be denatured reversibly in acidic guanidine hydrochloride, with the formation of poorly populated renaturation intermediates. In order to increase the accumulation of intermediates and to study the mechanism of ferritin renaturation, we analysed variants of the human ferritin H-chain altered at the N-terminus (delta(1-13)), near the 4-fold axis (Leu-169 --> Arg), the 3-fold axis (Asp-131 --> Ile + Glu-134 --> Phe) or the 2-fold axis (Ile-85 --> Cys). We also carried out specific chemical modifications of Cys-130 (near the 3-fold axis) and Cys-85 (near the 2-fold axis). Renaturation of the modified ferritins yielded assembly intermediates that differed in size and physical properties. Alterations of residues around the 2-, 4- and 3-fold axes produced subunit monomers, dimers and higher oligomers respectively. All these intermediates could be induced to assemble into ferritin 24-mers by concentrating them or by co-renaturing them with wild-type H-ferritin. The results support the hypothesis that the symmetric subunit dimers are the building blocks of ferritin assembly, and are consistent with a reassembly pathway involving the coalescence of dimers, probably around the 4-fold axis, followed by stepwise addition of dimers until the 24-mer cage is completed. In addition they show that assembly interactions are responsible for the large hysteresis of folding and unfolding plots. The implications of the studies for in vivo heteropolymer formation in vertebrates, which have two types of ferritin chain (H and L), are discussed.
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PMID:Effects of modifications near the 2-, 3- and 4-fold symmetry axes on human ferritin renaturation. 906 64

Non-heme diiron clusters occur in a number of enzymes (e.g., ribonucleotide reductase, methane monooxygenase, and Delta9-stearoyl-ACP desaturase) that activate O2 for chemically difficult oxidation reactions. In each case, a kinetically labile peroxo intermediate is believed to form when O2 reacts with the diferrous enzyme, followed by O-O bond cleavage and the formation of high-valent iron intermediates [formally Fe(IV)] that are thought to be the reactive oxidants. Greater kinetic stability of a peroxodiiron(III) intermediate in protein R2 of ribonucleotide reductase was achieved by the iron-ligand mutation Asp84 --> Glu and the surface mutation Trp48 --> Phe. Here, we present the first definitive evidence for a bridging, symmetrical peroxo adduct from vibrational spectroscopic studies of the freeze-trapped intermediate of this mutant R2. Isotope-sensitive bands are observed at 870, 499, and 458 cm-1 that are assigned to the intraligand peroxo stretching frequency and the asymmetric and symmetric Fe-O2-Fe stretching frequencies, respectively. Similar results have been obtained in the resonance Raman spectroscopic study of a peroxodiferric species of Delta9-stearoyl-ACP desaturase [Broadwater, J. A., Ai, J., Loehr, T. M., Sanders-Loehr, J., and Fox, B. G. (1998) Biochemistry 37, 14664-14671]. Similarities among these adducts and transient species detected during O2 activation by methane monooxygenase hydroxylase, ferritin, and wild-type protein R2 suggest the symmetrical peroxo adduct as a common intermediate in the diverse oxidation reactions mediated by members of this class.
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PMID:O2 activation by non-heme diiron proteins: identification of a symmetric mu-1,2-peroxide in a mutant of ribonucleotide reductase. 977 40


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