Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Mol Microbiol 2007 Jul
PMID:Disruption of iron homeostasis in Saccharomyces cerevisiae by high zinc levels: a genome-wide study. 1763 Sep 78

All regulatory processes require components that sense the environmental or metabolic conditions of the cell, and sophisticated sensory proteins have been studied in great detail. During the last few years, it turned out that enzymes can control gene expression in response to the availability of their substrates. Here, we review four different mechanisms by which these enzymes interfere with regulation in bacteria. First, some enzymes have acquired a DNA-binding domain and act as direct transcription repressors by binding DNA in the absence of their substrates. A second class is represented by aconitase, which can bind iron responsive elements in the absence of iron to control the expression of genes involved in iron homoeostasis. The third class of these enzymes is sugar permeases of the phosphotransferase system that control the activity of transcription regulators by phosphorylating them in the absence of the specific substrate. Finally, a fourth class of regulatory enzymes controls the activity of transcription factors by inhibitory protein-protein interactions. We suggest that the enzymes that are active in the control of gene expression should be designated as trigger enzymes. An analysis of the occurrence of trigger enzymes suggests that the duplication and subsequent functional specialization is a major pattern in their evolution.
Mol Microbiol 2008 Feb
PMID:Trigger enzymes: bifunctional proteins active in metabolism and in controlling gene expression. 1808 13

Friedreich's ataxia (FRDA) is a neurodegenerative disorder arising from a deficit of the mitochondrial iron chaperone, frataxin. Evidence primarily from yeast and mammalian cells is consistent with the hypothesis that a toxic hydroxyl radical generated from hydrogen peroxide (H2O2) via iron-catalyzed Fenton chemistry at least partially underlies the pathology associated with this disease. However, no whole-organism studies have been presented that directly test this hypothesis. We recently developed a Drosophila model that recapitulates the principal hallmarks of FRDA [Anderson PR, Kirby K, Hilliker A, Phillips JP (2005) Hum Mol Genet 14:3397-3405]. Using the Drosophila FRDA model, we now report that ectopic expression of enzymes that scavenge H2O2 suppresses the deleterious phenotypes associated with frataxin deficiency. In contrast, genetic augmentation with enzymes that scavenge superoxide is without effect. Augmentation of endogenous catalase restores the activity of the reactive oxygen species (ROS)-sensitive mitochondrial enzyme, aconitase and enhances resistance to H2O2 exposure, both of which are diminished by frataxin deficiency. Collectively, these data argue that H2O2 is an important pathogenic substrate underlying the phenotypes arising from frataxin deficiency in Drosophila and that interventions that reduce this specific ROS can effectively ameliorate these phenotypes. The therapeutic implications of these findings are clear and we believe warrant immediate clinical investigation.
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PMID:Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich's ataxia. 1818 3

Frataxin is a small conserved mitochondrial protein; in humans, mutations affecting frataxin expression or function result in Friedreich's ataxia. Much of the current understanding of frataxin function comes from informative studies with yeast models, but considerable debates remain with regard to the primary functions of this ubiquitous protein. We exploit the tractable reverse genetics of Trypanosoma brucei in order to specifically consider the importance of frataxin in an early branching lineage. Using inducible RNAi, we show that frataxin is essential in T. brucei and that its loss results in reduced activity of the marker Fe-S cluster-containing enzyme aconitase in both the mitochondrion and cytosol. Activities of mitochondrial succinate dehydrogenase and fumarase also decreased, but the concentration of reactive oxygen species increased. Trypanosomes lacking frataxin also exhibited a low mitochondrial membrane potential and reduced oxygen consumption. Crucially, however, iron did not accumulate in frataxin-depleted mitochondria, and as T. brucei frataxin does not form large complexes, it suggests that it plays no role in iron storage. Interestingly, RNAi phenotypes were ameliorated by expression of frataxin homologues from hydrogenosomes of another divergent protist Trichomonas vaginalis. Collectively, the data suggest trypanosome frataxin functions primarily only in Fe-S cluster biogenesis and protection from reactive oxygen species.
Mol Microbiol 2008 Jul
PMID:Ancestral roles of eukaryotic frataxin: mitochondrial frataxin function and heterologous expression of hydrogenosomal Trichomonas homologues in trypanosomes. 1843 47

One of the most important post-translational modifications is represented by phosphorylation on tyrosine, threonine and serine residues. Since abnormal phosphorylation is associated with various pathologies, it was of interest to perform a phosphoproteomic profiling of age-related skeletal muscle degeneration. We used the fluorescent phospho-specific Pro-Q Diamond dye to determine whether changes in the overall phosphorylation of the soluble skeletal muscle proteome differs significantly between young adult and senescent fibres. As an established model system of sarcopenia, we employed 30-month-old rat gastrocnemius fibres. Following the mass spectrometric identification of 59 major 2-D phosphoprotein landmark spots, the fluorescent dye staining survey revealed that 22 muscle proteins showed a differential expression pattern between 3-month- and 30-month-old muscle. Increased phosphorylation levels were shown for myosin light chain 2, tropomyosin alpha, lactate dehydrogenase, desmin, actin, albumin and aconitase. In contrast, decreased phospho-specific dye binding was observed for cytochrome c oxidase, creatine kinase and enolase. Thus, aging-induced alterations in phosphoproteins appear to involve the contractile machinery and the cytoskeleton, as well as the cytosolic and mitochondrial metabolism. This confirms that sarcopenia of old age is a complex neuromuscular pathology that is associated with drastic changes in the abundance and structure of key muscle proteins.
Int J Mol Med 2008 Jul
PMID:Phosphoproteomic analysis of aged skeletal muscle. 1857 73

Mitochondrial dysfunction and protein kinase C (PKC) activation are consistently found in diabetic cardiomyopathy but their relationship remains unclear. This study identified mitochondrial aconitase as a downstream target of PKC activation using immunoblotting and mass spectrometry, and then characterized phosphorylation-induced changes in its activity in hearts from type 1 diabetic rats. PKCbeta(2) co-immunoprecipitated with phosphorylated aconitase from mitochondria isolated from diabetic hearts. Augmented phosphorylation of mitochondrial aconitase in diabetic hearts was found to be associated with an increase in its reverse activity (isocitrate to aconitate), while the rate of the forward activity was unchanged. Similar results were obtained on phosphorylation of mitochondrial aconitase by PKCbeta(2) in vitro. These results demonstrate the regulation of mitochondrial aconitase activity by PKC-dependent phosphorylation. This may influence the activity of the tricarboxylic acid cycle, and contribute to impaired mitochondrial function and energy metabolism in diabetic hearts.
Cell Mol Life Sci 2009 Mar
PMID:Regulation of mitochondrial aconitase by phosphorylation in diabetic rat heart. 1915 62

Nordihydroguaiaretic acid (NDGA) is present in high concentrations in the desert shrub Creosote bush, Larrea tridentate. This plant has been used in traditional medicine because of its beneficial effects related, at least in part, to its antioxidant properties. Taking into account some evidence about neuroprotective effects elicited by NDGA, we evaluated the effect of this compound on the neurotoxicity induced by iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on cerebellar granule neurons. In addition, as reactive oxygen species play an important role in IAA-induced cytotoxicity, we also studied the enzymatic antioxidant system in IAA-treated cells. We found that IAA caused a dose-dependent decrease in cell viability of cultured neurons with an IC(50) of 18.4 microM and induced increased activity of catalase, glutathione peroxidase, and glutathione-S-transferase. Moreover, NDGA attenuated the toxicity induced by 18.4, 25, and 30 microM of IAA without abolishing the inhibitory effect of IAA on GAPDH activity. Furthermore, NDGA could prevent the inhibitory effect of IAA on aconitase activity, a marker of oxidative stress, suggesting that the protective effect of NDGA on IAA neurotoxicity was associated with the prevention of oxidative stress.
J Biochem Mol Toxicol
PMID:The effect of nordihydroguaiaretic acid on iodoacetate-induced toxicity in cultured neurons. 1936 47

Fumarase and aconitase in yeast are dual localized to the cytosol and mitochondria by a similar targeting mechanism. These two tricarboxylic acid cycle enzymes are single translation products that are targeted to and processed by mitochondrial processing peptidase in mitochondria prior to distribution. The mechanism includes reverse translocation of a subset of processed molecules back into the cytosol. Here, we show that either depletion or overexpression of Cit2 (cytosolic citrate synthase) causes the vast majority of fumarase to be fully imported into mitochondria with a tiny amount or no fumarase in the cytosol. Normal dual distribution of fumarase (similar amounts in the cytosol and mitochondria) depends on an enzymatically active Cit2. Glyoxylate shunt deletion mutations (Deltamls1, Deltaaco1 and Deltaicl1) exhibit an altered fumarase dual distribution (like in Deltacit2). Finally, when succinic acid, a product of the glyoxylate shunt, is added to the growth medium, fumarase dual distribution is altered such that there are lower levels of fumarase in the cytosol. This study suggests that the cytosolic localization of a distributed mitochondrial protein is governed by intracellular metabolite cues. Specifically, we suggest that metabolites of the glyoxylate shunt act as 'nanosensors' for fumarase subcellular targeting and distribution. The possible mechanisms involved are discussed.
Mol Microbiol 2009 Apr
PMID:Dual localization of fumarase is dependent on the integrity of the glyoxylate shunt. 1941 90

Fetal programming of adult disease is an area of research that has gained considerable attention. Epidemiological studies suggest that adverse intrauterine environment in fetal life is associated with a higher incidence of hypertension and coronary disease. Several mechanisms could contribute to these diseases and be regulated in a tissue-specific manner. The Na(+)-K(+)-ATPase, a membrane-bound enzyme, maintains the Na(+) and K(+) gradients across the plasma membrane of animal cells and therefore provides a mechanism for cell function regulation. Furthermore, in an in vitro model of cardiac hypertrophy, a decrease in the activity of the tricarboxylic acid (TCA) cycle enzyme, aconitase, was observed. We have shown that in our model of fetal programming, these two enzymes were regulated differently in heart and kidney of adult females.
Methods Mol Biol 2009
PMID:Renal and cardiac Na+-K +-ATPase and aconitase in a rat model of fetal programming. 1949 7

Friedreich's ataxia is a neurodegenerative disease caused by the low expression of frataxin, a mitochondrial iron-binding protein which plays an important, but non-essential, role in the formation of iron-sulfur (Fe/S) clusters. It has been shown that Yfh1, the yeast frataxin homologue, interacts functionally and physically with Isu1, the scaffold protein on which the Fe/S clusters are assembled. The large beta-sheet platform of frataxin is a good ligand candidate for this interaction. We have generated 12 yeast mutants in conserved residues of the beta-sheet protruding at the surface or buried in the protein core. The Q129A, I130A, W131A(F) and R141A mutations, which reside in surface exposed residues of the fourth and fifth beta-strands, result in severe cell growth inhibition on high-iron media and low aconitase activity, indicating that Fe/S cluster biosynthesis is impaired. The null phenotype of the I130A mutant results from the high instability of the protein, pointing that this buried residue is essential for folding. In contrast, Gln-129, Trp-131 and Arg-141 residues which are spatially closely clustered define a patch important for protein function. Co-immunoprecipitation experiments using cell extracts show that W131A, unlike W131F, is the sole mutation that strongly decreases the interaction with Isu1. Therefore, Trp-131, which is the only strictly conserved frataxin residue in all sequenced species, appears as a major contributor to the interaction with Isu1 through its surface-exposed aromatic side chain.
Hum Mol Genet 2010 Jan 15
PMID:Frataxin interacts with Isu1 through a conserved tryptophan in its beta-sheet. 1988 69


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