Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-free extracts prepared from spherical and rod-shaped cells of Arthrobacter crystallopoietes were assayed for enzymes during various periods of starvation. The level of NADH oxidase dropped to 20 and 30%, respectively, in spherical and rod-shaped cells during the first 1 to 2 days of starvation and then remained constant for 9 days. Catalase activity decreased continuously and reached a low level in 9 days. Enzymes involved in glucose metabolism and the tricarboxylic acid cycle were stable for the duration of the experiment (about 1 week). Succinic dehydrogenase, fumarase and aconitase were stable during 21 days of starvation, which is the longest time enzymes have been shown to be stable in any bacterium under conditions of total starvation.
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PMID:Stability of enzymes in starving Arthrobacter crystallopoietes. 18 Feb 37

Maintenance of cellular iron homeostasis demands the coordination of iron uptake, intracellular storage, and utilization. Recent investigations suggest that a single genetic regulatory system orchestrates the expression of proteins with central importance for all three aspects of cellular iron metabolism at the level of mRNA stability and translation. Two components of this regulatory system have been defined: a cis-acting mRNA sequence/structure motif called "iron-responsive element" (IRE) and a specific trans-acting cytoplasmic binding protein, here referred to as "IRE-binding protein" (IRE-BP). As an early event in the regulatory cascade, cellular iron deprivation induces the IRE-binding activity of IRE-BP, whereas binding activity is reduced in iron-replete cells. IRE-BP is highly homologous to the iron-sulphur (Fe-S) protein aconitase which strongly suggests that IRE-BP is an Fe-S protein itself. Control over IRE-BP activity by the cellular iron status is exerted post-translationally and likely involves changes between (4Fe-4S) and (3Fe-4S) states of the postulated IRE-BP Fe-S cluster. In addition, post-translational regulation of IRE-BP activity via heme has been proposed. Subsequent to its activation, IRE-BP binds with high affinity to single IREs contained in the 5' untranslated regions (UTRs) of ferritin and erythroid 5-aminolevulinic acid synthase (eALAS) mRNAs. The binding represses translation of these proteins involved in iron storage and utilization, respectively. In contrast, iron uptake is largely regulated via multiple IREs in the 3' UTR of transferrin receptor (TfR) mRNA. TfR-IREs are required for the iron-sensitive control of TfR mRNA stability. IRE-BP binding stabilizes TfR gene transcripts against as yet undefined ribonucleases. As a result of these regulatory interactions, iron starvation induces the expression of TfR, thereby increasing iron uptake, and represses the synthesis of proteins involved in iron storage and utilization. As cellular iron levels rise, the homeostatic balance is maintained by lowering iron uptake and increasing iron storage in ferritin.
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PMID:Coordination of cellular iron metabolism by post-transcriptional gene regulation. 143 80

The iron regulatory protein (IRP) is a cytoplasmic RNA-binding protein that regulates cellular iron metabolism at the posttranscriptional level. IRP is an unusual bifunctional molecule: in iron-replete cells it predominantly exists as a 4Fe-4S protein and exhibits aconitase enzymatic activity, whereas apo-IRP prevails in iron-starved cells and binds to iron-responsive elements (IREs), structural motifs within the untranslated regions of mRNAs involved in iron metabolism. A related protein with iron-regulated IRE-binding activity, IRPB, was previously identified in rodent cells. IRE-binding by IRP and IRPB is induced by iron deprivation and nitric oxide (NO). Controversial hypotheses have proposed that the induction of IRE-binding activity by iron results either from de novo synthesis of the apo-protein or from a posttranslational conversion of the Fe-S to the apo-protein form. This prompted a detailed analysis of how iron and NO regulate the RNA-binding activities of IRP and IRPB. We demonstrate that IRP is a relatively stable protein (half-life > 12 h). The induction of IRE-binding does not require de novo protein synthesis but results from conversion of Fe-S IRP to apo-IRP. In contrast, IRPB appears less stable in nonstarved cells (half-life approximately 4-6 h) and must be synthesized de novo following iron starvation. Our results furthermore reveal that two RNA-binding proteins with close structural and functional similarities that respond to the same cellular signals are regulated by predominantly different mechanisms.
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PMID:Differential regulation of two related RNA-binding proteins, iron regulatory protein (IRP) and IRPB. 758 45

Iron regulatory protein-1 (IRP-1) controls the expression of several mRNAs by binding to iron-responsive elements (IREs) in their untranslated regions. In iron-replete cells, a 4Fe-4S cluster converts IRP-1 to cytoplasmic aconitase. IRE binding activity is restored by cluster loss in response to iron starvation, NO, or extracellular H2O2. Here, we study the effects of intracellular quinone-induced oxidative stress on IRP-1. Treatment of murine B6 fibroblasts with menadione sodium bisulfite (MSB), a redox cycling drug, causes a modest activation of IRP-1 to bind to IREs within 15-30 min. However, IRE binding drops to basal levels within 60 min. Surprisingly, a remarkable loss of both IRE binding and aconitase activities of IRP-1 follows treatment with MSB for 1-2 h. These effects do not result from alterations in IRP-1 half-life, can be antagonized by the antioxidant N-acetylcysteine, and regulate IRE-containing mRNAs; the capacity of iron-starved MSB-treated cells to increase transferrin receptor mRNA levels is inhibited, and MSB increases the translation of a human growth hormone indicator mRNA bearing an IRE in its 5'-untranslated region. Nonetheless, MSB inhibits ferritin synthesis. Thus, menadione-induced oxidative stress leads to post-translational inactivation of both genetic and enzymatic functions of IRP-1 by a mechanism that lies beyond the "classical" Fe-S cluster switch and exerts multiple effects on cellular iron metabolism.
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PMID:Inactivation of both RNA binding and aconitase activities of iron regulatory protein-1 by quinone-induced oxidative stress. 1003 8

Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal transferrin receptor, which bears no structural similarity with mammalian transferrin receptors, is regulated by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulation of the transferrin receptor and a 3-fold increase of the transferrin uptake rate. The abundance of expression site associated gene product 6 (ESAG6) mRNA, which encodes one of the two subunits of the trypanosome transferrin receptor, is regulated 5-fold by a post-transcriptional mechanism. In mammalian cells the stability of transferrin receptor mRNA is controlled by iron regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytoplasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was investigated. Iron regulation of the transferrin receptor was found to be unaffected in Deltaaco::NEO/Deltaaco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of post-transcriptional transferrin receptor regulation in trypanosomes appears to be distinct from the IRE/IRP paradigm. The transferrin uptake rate was also increased when trypanosomes were transferred from medium supplemented with foetal bovine serum to medium supplemented with sera from other vertebrates. Due to varying binding affinities of the trypanosomal transferrin receptor for transferrins of different species, serum change can result in iron starvation. Thus, regulation of transferrin receptor expression may be a fast compensatory mechanism upon transmission of the parasite to a new host species.
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PMID:Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei. 1047 81

Posttranscriptional regulation of iron homeostasis involves, among other factors, a reversible conversion of the Fe-S enzyme cytoplasmic aconitase to a mRNA-binding iron regulatory protein (IRP-1) that lacks an Fe-S cluster. Previous studies have shown that aconitase/IRP-1 may be a target of *NO or peroxynitrite (ONOO(-)), formed after reaction of *NO with superoxide anion (O(2)(*-)); however, the mechanisms and consequences of such interactions have remained uncertain. In this study, recombinant aconitase/IRP-1 was exposed to SIN-1, whose thermal decomposition releases *NO and O(2)(*-). Results showed that SIN-1 was able to induce concomitant inactivation of aconitase and activation of IRP-1, attributable to cluster disassembly induced by ONOO(-). SIN-1 was used also in lysates of J774A.1 mouse macrophages grown under control conditions, or subjected to iron loading or starvation by treatment with hemin or desferrioxamine, respectively. Three lines of evidence confirmed that ONOO(-) activated IRP-1 by removing iron from the Fe-S cluster of cytoplasmic aconitase. First, IRP-1 activation was accompanied by iron release and loss of aconitase activity. Second, aconitase activity was recovered by reassembling Fe-S clusters with cysteine and ferrous ammonium sulfate. Third, iron release and IRP-1 activation were observed in lysates from control or iron-loaded macrophages, containing increasing levels of Fe-S clusters, but not in lysates from iron-starved macrophages, in which aconitase had already undergone cluster disassembly and switched to IRP-1. *NO was less efficient than ONOO(-) in attacking the Fe-S cluster of cytoplasmic aconitase; in fact, SIN-1-dependent iron release and IRP-1 activation were diminished by superoxide dismutase, which scavenged O(2)(*-) before it reacted with *NO to form ONOO(-). Under comparable conditions, however, both *NO and ONOO(-) inactivated an IRP-2 unable to assemble an Fe-S cluster. These results indicate that *NO and ONOO(-) may activate IRP-1 by attacking the Fe-S cluster of cytoplasmic aconitase, while also inactivating the cluster-deficient IRP-2. Such divergent actions offer clues to explain links between iron homeostasis and reactive nitrogen species in macrophages involved in inflammation or other pathophysiologic conditions.
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PMID:Nitric oxide and peroxynitrite activate the iron regulatory protein-1 of J774A.1 macrophages by direct disassembly of the Fe-S cluster of cytoplasmic aconitase. 1204 77

Induction of the activity of aconitate hydratase (AH) was observed in rat hepatocytes under the conditions of food deprivation. The increase in AH activity after 4 days of starvation in the studied tissues was from 0.57 to 2.05 U/g crude liver weight. The induction of aconitase was associated both with the cytoplasmic and mitochondrial AH isoforms. The activities of cytosolic and mitochondrial AH isoforms in starving animals consisted of 83 and 17% of the total activity, respectively. The cytoplasmic and mitochondrial isoforms of the enzyme with specific activities 11.1 and 6.13 U/mg protein, respectively, were obtained by a five-step purification procedure that included fractionation with ammonium sulfate, ion-exchanging chromatography on DEAE-Toyopearl and gel filtration. The purified preparations of these AH isoforms were electrophoretically homogenous. The molecular weights of these isoforms were estimated and several kinetic and regulatory properties were studied.
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PMID:Induction of aconitate hydratase in hepatocytes of starving rats. 1213 79

The mRNA level of the aconitase gene acn of Corynebacterium glutamicum is reduced under iron limitation. Here we show that an AraC-type regulator, termed RipA for "regulator of iron proteins A," is involved in this type of regulation. A C. glutamicum DeltaripA mutant has a 2-fold higher aconitase activity than the wild type under iron limitation, but not under iron excess. Comparison of the mRNA profiles of the DeltaripA mutant and the wild type revealed that the acn mRNA level was increased in the DeltaripA mutant under iron limitation, but not under iron excess, indicating a repressor function of RipA. Besides acn, some other genes showed increased mRNA levels in the DeltaripA mutant under iron starvation (i.e. those encoding succinate dehydrogenase (sdhCAB), nitrate/nitrite transporter and nitrate reductase (narKGHJI), isopropylmalate dehydratase (leuCD), catechol 1,2-dioxygenase (catA), and phosphotransacetylase (pta)). Most of these proteins contain iron. Purified RipA binds to the upstream regions of all operons mentioned above and in addition to that of the catalase gene (katA). From 13 identified binding sites, the RipA consensus binding motif RRGCGN(4)RYGAC was deduced. Expression of ripA itself is repressed under iron excess by DtxR, since purified DtxR binds to a well conserved binding site upstream of ripA. Thus, repression of acn and the other target genes indicated above under iron limitation involves a regulatory cascade of two repressors, DtxR and its target RipA. The modulation of the intracellular iron usage by RipA supplements mechanisms for iron acquisition that are directly regulated by DtxR.
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PMID:The AraC-type regulator RipA represses aconitase and other iron proteins from Corynebacterium under iron limitation and is itself repressed by DtxR. 1617 44

Mitochondrial ferritin (MtFt) is a mitochondrial iron-storage protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular iron homeostasis in mammalian cells. Using tumor xenografts, we examined the effects of MtFt overexpression on tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted tumor growth in nude mice. Mitochondrial iron deposition in MtFt-expressing tumors was directly observed by transmission electron microscopy. A cytosolic iron starvation phenotype in MtFt-expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins, and concomitantly both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to decreases in total cellular heme content and heme oxygenase-1 levels. In addition, elevated MtFt in tumors was also associated with a decrease in total aconitase activity and lower frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partially deficient heme and iron-sulfur cluster synthesis. It is likely that deprivation of iron in the cytosol is the cause for the significant inhibition of xenograft tumor growth.
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PMID:In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin. 1675 84

Zinc is an essential metal that, when in excess, can be deleterious to the cell. Therefore, homeostatic mechanisms for this cation must be finely tuned. To better understand the response of yeast in front of an excess of zinc, we screened a systematic deletion mutant library for altered growth in the presence of 6 mM zinc. Eighty-nine mutants exhibited increased zinc sensitivity, including many genes involved in vacuolar assembling and biogenesis. Interestingly, a mutant lacking the Aft1 transcription factor, required for the transcriptional response to iron starvation, was found to be highly sensitive to zinc. Genome-wide transcriptional profiling revealed that exposure to 5 mM ZnCl(2) results in rapid increase in the expression of numerous chaperones required for proper protein folding or targeting to vacuole and mitochondria, as well as genes involved in stress response (mainly oxidative), sulphur metabolism and some components of the iron regulon. The effect of the lack of Aft1 both in the absence and in the presence of zinc overload was also investigated. Exposure to high zinc generated reactive oxygen species and markedly decreased glutathione content. Interestingly, zinc excess results in decreased intracellular iron content and aconitase and cytochrome c activities in stationary-phase cultures. These findings suggest that high zinc levels may alter the assembly and/or function of iron-sulphur-containing proteins, as well as the biosynthesis of haem groups, thus establishing a link between zinc, iron and sulphur metabolism.
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PMID:Disruption of iron homeostasis in Saccharomyces cerevisiae by high zinc levels: a genome-wide study. 1763 Sep 78


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