UNIPROT:P02794 - FACTA Search

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

Recent studies reported that iron salts were absorbed in the duodenum utilizing a pathway involving membrane-associated integrin and a cytosolic protein named mobilferrin. In addition, a large molecular weight cytoplasmic complex was labeled with radioiron during mucosal uptake of iron in the duodenum. The molecular mass of this protein was 520 000 daltons, slightly larger than ferritin. On denaturing SDS-PAGE, the purified protein complex appeared to consist of at least four polypeptides, closely associated with each other. This complex was called paraferritin because its hydrodynamic volume resembled ferritin. In the present work, antibody studies demonstrate the presence of integrin, mobilferrin, and flavin monooxygenase in the water-soluble complex. Biochemical studies demonstrate the presence of a NADPH-dependent flavin monooxygenase ferrireductase activity that reduces Fe(III) to Fe(II). Antibodies against either integrin or mobilferrin inhibit monooxygenase activity. Inhibition of monooxygenase activity decreases radioiron uptake by tissue culture intestinal cells. Thus, we postulated that paraferritin plays a role in the mucosal uptake and transport of inorganic iron in small intestinal absorptive cells and is a mechanism for both the internalization of integrin from membranes to cellular cytosol and the delivery of iron to cellular constituents in an appropriate redox state.
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PMID:Paraferritin: a protein complex with ferrireductase activity is associated with iron absorption in rats. 863 93

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 the major storage form of iron within cells, and iron released from ferritin has been shown to stimulate lipid peroxidation. Microsomes from rats chronically fed ethanol are more active in generating reactive oxygen intermediates than control microsomes. Since superoxide is one of the reductants capable of releasing iron from ferritin, and superoxide generation by microsomes is increased after chronic ethanol treatment, the ability of ferritin to stimulate lipid peroxidation of microsomes isolated from control rats and rats treated chronically with ethanol was evaluated. Ferritin was much more effective in stimulating lipid peroxidation of microsomes after ethanol treatment; net increases in thiobarbituric acid-reactive components by ferritin were 4-fold greater in the presence of NADPH with microsomes from the ethanol-treated rats compared to pair-fed controls and 10-fold greater with NADH as the microsomal reductant. Net increases in chemiluminescence by ferritin were about 10-fold greater with microsomes from the ethanol-treated rats. The NADPH- and NADH-dependent increases in lipid peroxidation produced by ferritin were prevented by superoxide dismutase, which lowered the rates found in the presence of ferritin to values found in the absence of ferritin. Catalase and hydroxyl radical scavengers had no effect on the stimulation by ferritin. Nonheme iron chelators prevented the ferritin stimulation as did glutathione, propylgallate, and trolox. Basal rates of lipid peroxidation were inhibited by anti-CYP2E1 IgG; the stimulation by ferritin was decreased by anti-CYP2E1 IgG. These results show that microsomes from ethanol-fed rats are more reactive than control microsomes in interacting with ferritin to produce oxidants capable of catalyzing lipid peroxidation. The inhibition of the ferritin-catalyzed lipid peroxidation by superoxide dismutase and anti-CYP2E1 IgG is consistent with a role for CYP2E1-generated superoxide radical in mobilizing iron from ferritin and in the subsequent catalysis of lipid peroxidation. Since ferritin is the major cellular storage form of iron, increased mobilization of iron from ferritin by CYP2E1-derived superoxide radical may play a role in the development of oxidative stress after ethanol treatment.
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PMID:Ferritin stimulation of lipid peroxidation by microsomes after chronic ethanol treatment: role of cytochrome P4502E1. 880 16

The in vivo production of HO- requires iron ions, H2O2 and O2- or other oxidants but probably does not occur through the Haber-Weiss reaction. Instead oxidants, such as O2-, increase free iron by releasing Fe(II) from the iron-sulfur clusters of dehydratases and by interfering with the iron-sulfur clusters reassembly. Fe(II) then reduces H2O2, and in turn Fe(III) and the oxidized cluster are re-reduced by cellular reductants such as NADPH and glutathione. In this way, SOD cooperates with cellular reductants in keeping the iron-sulfur clusters intact and the rate of HO. production to a minimum. O2- and other oxidants can release iron from Fe(II)-containing enzymes as well as copper from thionein. The released Fe(III) and Cu(II) are then reduced to Fe(II) and Cu(I) and can then participate in the Fenton reaction. In mammalian cells oxidants are able to convert cytosolic aconitase into active IRE-BP, which increases the "free" iron concentration intracellularly both by decreasing the biosynthesis of ferritin and increasing biosynthesis of transferrin receptors. The biological role of the soxRS regulon of Escherichia coli, which is involved in the adaptation toward oxidative stress, is presumably to counteract the oxidative inactivation of the iron clusters and the subsequent release of iron with consequent increased rate of production of HO.
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PMID:The role of iron-sulfur clusters in in vivo hydroxyl radical production. 890 35

Experiments were carried out to evaluate the effect of nitric oxide exposure on the ability of NADPH-dependent microsomal electron transfer to mobilize iron from ferritin. Such interactions could play a role in potential antioxidant actions of nitric oxide (NO). Preincubation of the microsomes from phenobarbital-treated rats with NO donors such as S-nitroso-D,L-N-acetyl penicillamine (SNAP), S-nitroso-L-glutathione, SIN-1, and DETANONOate followed by centrifugation, washing, and resuspension of the microsomes resulted in a decrease in the ferritin-dependent oxidation of 2',7'-dichlorofluorescein diacetate (DCFDA) or ferritin-catalyzed chemiluminescence compared to microsomes pretreated with buffer. The ferritin-stimulated rate of oxidation of DCFDA or of chemiluminescence was completely restored if the microsomal preincubation with NO donors was performed in the presence of hemoglobin. In contrast to results with ferritin, ferric-stimulated oxidation of the dye was not affected by any of the tested NO donors. The microsomal oxidation of aminopyrine was inhibited after SNAP treatment, indicating that NO inhibited cytochrome P450 catalyzed activity. Inhibition of cytochrome P450 also resulted in an inhibition of microsomal production of superoxide. Similar results were obtained using microsomes from a cloned cell line which express the CYP2E1 isoform. Since superoxide is required for the mobilization of iron from ferritin by microsomes, inhibition of superoxide production as a consequence of NO interaction with cytochrome P450 is likely to be responsible for the prevention of ferritin-catalyzed formation of reactive oxygen species by NO donors. The results suggest that NO could exhibit an antioxidant capacity through its ability of decreasing the activity of iron-heme compounds, such as cytochrome P450, preventing the release of catalytically active iron from ferritin, and thus decreasing the ability to generate oxygen free radicals involved in cytotoxicity.
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PMID:Inhibition of ferritin-stimulated microsomal production of reactive oxygen intermediates by nitric oxide. 912 72

Neutrophil influx into tissues occurs in many diverse diseases and can be associated with both beneficial and injurious effects. We hypothesize that the stimulus for certain neutrophilic inflammatory responses can be reduced to a series of competing reactions for iron, with either a labile or reactive coordination site available, between host chelators and chelators not indigenous to that specific living system. The iron focuses the transport of host phagocytic cells through a metal catalyzed generation of oxidant sensitive mediators including cytokines and eicosanoids. Many of these products are chemotactic for neutrophils. We also postulate that the iron increases the activity of the phagocyte associated NADPH oxidoreductase in the neutrophil. The function of this enzyme is likely to be the generation of superoxide in the host's attempt to chemically reduce and dislodge the iron from its chelate complex. After the reoxidation of Fe2+ in an aerobic environment, Fe3+ will be coordinated by host lactoferrin released by the neutrophil. When complexed by this glycoprotein, the metal does not readily undergo oxidation/reduction and is safely transported to the macrophages of the reticuloendothelial system where it is stored in ferritin. Finally, we propose that the neutrophil will attempt to destroy the chelator not indigenous to the host by releasing granular contents other than lactoferrin. Inability to eliminate the chelator allows this sequence to repeat itself, which can lead to tissue injury. Such persistence of a metal chelate in the host may be associated with biomineralization, fibrosis, and cancer.
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PMID:Hypothesis: iron chelation plays a vital role in neutrophilic inflammation. 921 Feb 96

Anticancer therapy with doxorubicin (DOX) is limited by severe cardiotoxicity, presumably reflecting the intramyocardial formation of drug metabolites that alter cell constituents and functions. In a previous study, we showed that NADPH-supplemented cytosolic fractions from human myocardial samples can enzymatically reduce a carbonyl group in the side chain of DOX, yielding a secondary alcohol metabolite called doxorubicinol (DOXol). Here we demonstrate that DOXol delocalizes low molecular weight Fe(II) from the [4Fe-4S] cluster of cytoplasmic aconitase. Iron delocalization proceeds through the reoxidation of DOXol to DOX and liberates DOX-Fe(II) complexes as ultimate by-products. Under physiologic conditions, cluster disassembly abolishes aconitase activity and forms an apoprotein that binds to mRNAs, coordinately increasing the synthesis of transferrin receptor but decreasing that of ferritin. Aconitase is thus converted into an iron regulatory protein-1 (IRP-1) that causes iron uptake to prevail over sequestration, forming a pool of free iron that is used for metabolic functions. Conversely, cluster reassembly converts IRP-1 back to aconitase, providing a regulatory mechanism to decrease free iron when it exceeds metabolic requirements. In contrast to these physiologic mechanisms, DOXol-dependent iron release and cluster disassembly not only abolish aconitase activity, but also affect irreversibly the ability of the apoprotein to function as IRP-1 or to reincorporate iron within new Fe-S motifs. This damage is mediated by DOX-Fe(II) complexes and reflects oxidative modifications of -SH residues having the dual role to coordinate cluster assembly and facilitate interactions of IRP-1 with mRNAs. Collectively, these findings describe a novel mechanism of cardiotoxicity, suggesting that intramyocardial formation of DOXol may perturb the homeostatic processes associated with cluster assembly or disassembly and the reversible switch between aconitase and IRP-1. These results may also provide a guideline to design new drugs that mitigate the cardiotoxicity of DOX.
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PMID:The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein-1 in cytosolic fractions from human myocardium. 957 81

Rat liver DT-diaphorase (EC 1.6.99.2) catalyzed reductive N-denitration of tetryl (2,4,6-tri-nitrophenyl-N-methylnitramine) and 2,4-dinitrophenyl-N-methylnitramine, oxidizing the excess of NADPH. The reactions were accompanied by oxygen consumption and superoxide dismutase-sensitive reduction of added cytochrome c and reductive release of Fe2+ from ferritin. Quantitatively, the reactions of DT-diaphorase proceeded like single-electron reductive N-denitration of tetryl by ferredoxin:NADP+ reductase (EC 1.18.1.2) (Shah, M.M. and Spain, J.C. (1996) Biochem. Biophys. Res. Commun. 220, 563-568), which was additionally checked up in this work. Thus, although reductive N-denitration of nitrophenyl-N-nitramines is a net two-electron (hydride) transfer process, DT-diaphorase catalyzed the reaction in a single-electron way. These data point out the possibility of single-electron transfer steps during obligatory two-electron (hydride) reduction of quinones and nitroaromatics by DT-diaphorase.
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PMID:DT-diaphorase catalyzes N-denitration and redox cycling of tetryl. 978 67

A novel NADH-dependent, soluble flavoreductase of 60 kDa, active toward ferric chelates and quinones, has been purified from maize seedlings. Two closely related isoforms were separated. The two isoforms are similar in several biochemical features, with the exception of the apparent molecular mass of their subunits (29 and 31 kDa, respectively). They are homodimers in the native state, they bind FAD as the prosthetic group and show strong preference for NADH over NADPH as the electron donor. Ferric chelates (chiefly ferric citrate, Km 3-5 x 10(-5) M; kcat/Km 3.4-3.7 x 10(5) M-1 s-1), and some quinones (benzoquinone, coenzyme Q-0, and juglone) are used as electron acceptors. Enzymatic reduction of benzoquinone occurs with formation of radical semiquinones. Both soluble ferric chelate reductase isoforms are strongly inhibited by p-hydroxymercuribenzoic acid (I50 5 nM) and by cibachron blue, the latter giving nonlinear inhibition. It is suggested that soluble ferric chelate reductase might be involved in the symplastic reduction of iron chelates which is required for the assembly of iron-containing macromolecules such as cytochromes and ferritin.
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PMID:Characterization of a novel NADH-specific, FAD-containing, soluble reductase with ferric citrate reductase activity from maize seedlings. 1006 52

NADPH-P450 oxidoreductase (CPR) is essential for the activity of cytochrome P450 (P450). Previous studies demonstrated that CPR regulates the levels of various P450 isoforms in vitro. We investigated the mechanistic basis for this regulation. By transfection of Chinese hamster ovary DUKXB11 cells we obtained the cell line DUKX/2D6, which expressed human CYP2D6, a P450 isoform. Subsequently, DUKX/2D6 cells were transfected with human CPR cDNA to generate the cell line DUKX/2D6/CPR-3. Expression of recombinant CPR decreased the level of spectrally detectable CYP2D6 holoprotein in DUKX/2D6/CPR-3 cells by 70%, whereas the level of immunodetectable apoprotein remained unchanged. Addition of the radical scavenger DMSO increased levels of CYP2D6 holoenzyme in DUKX/2D6/CPR-3 cells but not in DUKX/2D6 cells. A similar effect was noted when cells were grown in the presence of hemin. Importantly, combined treatment with DMSO and hemin increased levels of CYP2D6 holoenzyme in DUKX/2D6/CPR-3 but not in DUKX/2D6 cells even further than either treatment alone. None of these treatments affected the level of immunodetectable CYP2D6. This demonstrates that expression of CPR increases production of damaging radicals but also that CPR may alter haem homoeostasis. In agreement with this, the activity of haem oxygenase, a rate-limiting enzyme in haem metabolism, was compared with that in DUKX/DHFR control cells (expressing dihydrofolate reductase), and was 3-fold higher in DUKX/2D6/CPR-3 but similar in DUKX/2D6 cells. Furthermore, treatment of cells with sodium arsenite increased levels of haem oxygenase concomitant with a marked decrease of spectrally detectable CYP2D6 and a rise in levels of ferritin, which sequesters free iron released from the destruction of haem. These data demonstrate that CPR regulates P450 activity by supplying electrons and also by altering P450 levels via radical-and haem oxygenase-mediated pathways.
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PMID:Human NADPH-P450 oxidoreductase modulates the level of cytochrome P450 CYP2D6 holoprotein via haem oxygenase-dependent and -independent pathways. 1136 92

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