Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extract of jaman pulp from fruit of Eugenia jambolana showed hypoplycemic activity. This report is the first evidence of such activity in relation to pulp. The effect of pulp was seen in 30 min, while the seeds of the same fruit required 24 hr. The extracts of bark of Ficus bengalensis caused reduction in blood sugar level. These results were confirmed in streptozotocin-induced diabetic animals. The oral administration of the extract resulted in enhancement in serum insulin levels in normoglycemic and diabetic rats. The incubation of isolated islets of Langerhans from normal as well as from diabetic animals with each of these plant extracts stimulated insulin secretion. These extracts inhibited insulinase activity from liver and kidney.
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PMID:Hypoglycemic activity of Eugenia jambolana and Ficus bengalensis: mechanism of action. 176 83

The insulin-degrading enzyme (IDE) is an evolutionarily conserved enzyme that has been implicated in cellular insulin degradation, but its site of action and importance in regulating insulin degradation have not been clearly established. We addressed this question by examining the effects of overexpressing IDE on insulin degradation in COS cells, using both human IDE (hIDE) and its Drosophila homolog (dIDE). The dIDE, which was recently cloned in our laboratory, has 46% amino acid identity with hIDE, degrades insulin with comparable efficiency, and is readily expressed in mammalian cells. Transient expression of dIDE or hIDE in COS monkey kidney cells led to a 5- to 7-fold increase in the rate of degradation of extracellular insulin, indicating that IDE can regulate cellular insulin degradation. Insulin-degrading activity in the medium was very low and could not account for the difference between transfected and control cells. To further localize the site of IDE action, the fate of insulin after receptor binding was examined. The dIDE-transfected cells displayed increased degradation of prebound insulin compared to control cells. This increase in degradation was observed even when excess unlabeled insulin was added to block reuptake or extracellular degradation. These results indicate that IDE acts at least in part within the cell. The lysosomotropic agents chloroquine and NH4Cl did not affect the increase in insulin degradation produced by transfection with dIDE, indicating that the lysosomal and IDE-mediated pathways of insulin degradation are independent. The results demonstrate that IDE can regulate the degradation of insulin by intact cells via an intracellular pathway.
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PMID:Regulation of insulin degradation: expression of an evolutionarily conserved insulin-degrading enzyme increases degradation via an intracellular pathway. 177 31

A cytosolic protein specifically binding to and degrading atrial natriuretic peptide (ANP) was purified from rat brain homogenate. Based on partial amino acid sequences and enzymatic properties, this protein with an apparent molecular mass of 112 kDa has been identified as the rat insulin-degrading enzyme (IDE). In addition to the known substrates, insulin and transforming-growth-factor alpha IDE binds also with high affinity (apparent Kd 60 nM) to ANP. Competition studies with structural variants of ANP demonstrate that both the C terminus and the disulfide loop of the molecule are essential for high-affinity binding. The data suggest that IDE might be involved in the cellular processing and/or metabolic clearance of ANP.
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PMID:Atrial natriuretic peptide (ANP) is a high-affinity substrate for rat insulin-degrading enzyme. 183 94

The mechanisms by which growth factors are degraded and the role this process plays in the regulation of cell growth are not well understood. Insulin degradation is believed to be mediated by a specific metalloprotease, insulin-degrading enzyme (IDE). We have previously shown that IDE can also degrade transforming growth factor-alpha (TGF alpha), but not epidermal growth factor (EGF), in vitro. This selectivity was surprising, since TGF alpha and EGF are structurally similar and bind to the same receptor with comparable affinities. Using a spectrum of protease inhibitors, we have now analyzed the degradation of TGF alpha, EGF, and insulin by human hepatoma HepG2 cells. The results suggest that bacitracin-sensitive metalloproteases are involved in the degradation of TGF alpha and EGF as well as insulin, and that the degradation of TGF alpha, but not EGF, is mediated in part by IDE. Inhibiting the activity of these metalloproteases decreased growth factor depletion, suggesting that these enzymes play an important role in the control of extracellular growth factor levels. The existence of separate degradative pathways for EGF and TGF alpha may explain how the two factors exert differential effects in some systems, and degradation of TGF alpha by IDE would provide a possible mechanism for interaction between the insulin and TGF alpha/EGF signalling systems.
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PMID:Regulation of insulin, epidermal growth factor, and transforming growth factor-alpha levels by growth factor-degrading enzymes. 184 63

Haemoglobin damaged by exposure of red blood cells to oxidants is rapidly degraded by a proteolytic pathway which does not require ATP [Fagan, Waxman & Goldberg (1986) J. Biol. Chem. 261, 5705-5713]. By fractionating erythrocyte lysates, we have purified two proteases which hydrolyse oxidatively damaged haemoglobin (Ox-Hb). One protease hydrolysed small fluorogenic substrates in addition to Ox-Hb. Its molecular mass was approximately 700 kDa and it consisted of several subunits ranging in size from 22 to 30 kDa. This enzyme may be related to the high-molecular-mass multicatalytic proteinase previously isolated from a variety of tissue and cell types. The other Ox-Hb-degrading activity had an apparent molecular mass of 400 kDa on gel filtration, a subunit size of 110 kDa and an isoelectric point between 4.5 and 5.0. This protease also hydrolysed the small polypeptides insulin and glucagon, as well as other large proteins such as lysozyme. Insulin blocked the degradation of Ox-Hb and Ox-Hb blocked the hydrolysis of insulin by the purified protease. Thiol reagents and metal chelators strongly inhibited the hydrolysis of both Ox-Hb and insulin, whereas inhibitors of serine, aspartic and thiol proteases had little effect. These properties suggest that the Ox-Hb-degrading activity purified from rabbit erythrocytes is the cytosolic insulin-degrading enzyme that is believed to play a role in the metabolism of insulin in several tissues. We propose that this enzyme may also function as a key component in a cytoplasmic degradative pathway responsible for removing proteins damaged by oxidants.
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PMID:Purification of a protease in red blood cells that degrades oxidatively damaged haemoglobin. 187 13

The nature of insulin degradation within endosomes was studied in vitro. Radiolabeled insulin was perfused into rat liver via the portal vein, and insulin-containing endosomes were prepared by differential centrifugation. The endosomes were incubated in various buffers, and hormone degradation was monitored by Sephadex G-50 chromatography and high-performance liquid chromatography (HPLC). Endosomes incubated in simple imidazole or HEPES (pH 7.4) buffers rapidly degraded insulin to intermediate- and then to low-molecular-weight products that were lost from the vesicles. HPLC analysis of insulin-sized material showed the products to be the same as those produced by intact cells. The endosomes did not acidify in these buffers (as assessed by the acridine orange method), and ATP had no effects. When the endosomes were incubated in a chloride-containing buffer, degradation was greatly inhibited, and acidification did not occur. Both insulin degradation and acidification were activated when Mg-ATP was added to this buffer system. HPLC analysis of the products generated in this system revealed not only typical cellular products but additional less hydrophobic products. Western-blot analysis of endosomal protein with anti-insulin-degrading enzyme antibody showed this enzyme to be present. In conclusion, isolated endosomes rapidly and completely degrade insulin through products that are typical of cellular degradation without requiring acidification. Chloride-containing buffers inhibit endosomal degradation, which is reversed by Mg-ATP, but this system does not mimic cellular degradation. At least one of the enzymes responsible for insulin degradation is insulin-degrading enzyme.
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PMID:Degradation of intraendosomal insulin by insulin-degrading enzyme without acidification. 201 43

On the basis of a statistical analysis of an alignment of the amino acid sequences, a new superfamily of metalloendopeptidases is proposed, consisting of human insulinase, Escherichia coli protease III and mitochondrial processing endopeptidases from Saccharomyces and Neurospora. These enzymes do not contain the 'HEXXH' consensus sequence found in all previously recognized zinc metalloendopeptidases.
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PMID:Homologues of insulinase, a new superfamily of metalloendopeptidases. 202 23

We have previously identified and characterized a metalloproteinase from Drosophila that cleaves insulin and transforming growth factor-alpha, but not epidermal growth factor, at physiological concentrations. On the basis of enzymatic properties and substrate specificity, this enzyme was identified as the Drosophila homolog of the mammalian insulin-degrading enzyme (IDE). We now report the cloning and sequencing of the cDNA coding for the Drosophila IDE (dIDE). Northern blot analysis indicates that the dIDE is translated from a 3.6-kilobase transcript similar in size to one of the two human IDE transcripts. The gene for the dIDE has been mapped to chromosome 3L (77B). The sequence of the dIDE is very similar to that of the human IDE, and both enzymes share limited but significant identity with the bacterial metalloproteinase protease III. Indirect studies based upon inhibitors, degradation products, and microinjected antibodies have suggested that the IDE can initiate cellular insulin degradation in mammalian cells. To determine whether dIDE expressed in mammalian cells can also degrade insulin, we transfected the cDNA into murine NIH3T3 cells. Extracts of the transfected cells showed increased insulin-degrading activity, demonstrating that the dIDE can be functionally expressed in mammalian cells. These results indicate that the properties of the IDE are evolutionarily conserved.
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PMID:Cloning and expression of the cDNA for a Drosophila insulin-degrading enzyme. 212 97

Insulin-degrading and insulinase-inhibiting activity of whole blood and erythrocytes of 146 children affected with acute leucosis of different stages were investigated. No statistically reliable difference between the data of insulin-degrading activity in acute leucosis and healthy children was found. Insulinase-inhibiting activity of both the hemolysate of blood and erythrocytes was increased in children in the active stage of the disease.
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PMID:Insulin-degrading activity and insulinase-inhibiting activity in acute leukemia. 219 Dec 53

Upon reduction of serum in their media, mouse BC3H1 muscle cells withdraw from the cell cycle and begin to differentiate. In differentiating cells, the induction of muscle-specific genes is accompanied by a distinct morphological chance. However, differentiated BC3H1 cells do not fuse with each other; they remain mononucleated. Metalloendoprotease inhibitors selectively block the differentiation of BC3H1 cells while inhibitors of other protease types are ineffective. In these cells, the degradation of the internalized insulin is initiated by a 110 kDa, non-lysosomal protease known as the insulin-degrading enzyme. The same metalloendoprotease inhibitors that block BC3H1 differentiation also inhibit, with a similar specificity and potency, the in vitro and the in vivo degradation of insulin by the insulin-degrading enzyme. When the serum in the medium is reduced, the activity of the insulin-degrading enzyme in the cell cytoplasm increases rapidly. This increase precedes any detectable change in the differentiation state of these cells by about 12 hours. These results, together with very similar ones obtained with primary rat skeletal muscle cells, support our earlier proposal that the insulin-degrading enzyme is the metalloendoprotease involved in the initiation of the morphological and biochemical differentiation of muscle cells in culture.
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PMID:Differentiation of BC3H1 and primary skeletal muscle cells and the activity of their endogenous insulin-degrading enzyme are inhibited by the same metalloendoprotease inhibitors. 226 83


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