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

The endosomal compartment of hepatic parenchymal cells contains an acidic endopeptidase, endosomal acidic insulinase, which hydrolyzes internalized insulin and generates the major primary end product A(1--21)-B(1--24) insulin resulting from a major cleavage at residues Phe(B24)-Phe(B25). This study addresses the nature of the relevant endopeptidase activity in rat liver that is responsible for most receptor-mediated insulin degradation in vivo. The endosomal activity was shown to be aspartic acid protease cathepsin D (CD), based on biochemical similarities to purified CD in 1) the rate and site of substrate cleavage, 2) pH optimum, 3) sensitivity to pepstatin A, and 4) binding to pepstatin A-agarose. The identity of the protease was immunologically confirmed by removal of greater than 90% of the insulin-degrading activity associated with an endosomal lysate using polyclonal antibodies to CD. Moreover, the elution profile of the endosomal acidic insulinase activity on a gel-filtration TSK-GEL G3000 SW(XL) high performance liquid chromatography column corresponded exactly with the elution profile of the immunoreactive 45-kDa mature form of endosomal CD. Using nondenaturating immunoprecipitation and immunoblotting procedures, other endosomal aspartic acid proteases such as cathepsin E and beta-site amyloid precursor protein-cleaving enzyme (BACE) were ruled out as candidate enzymes for the endosomal degradation of internalized insulin. Immunofluorescence studies showed a largely vesicular staining pattern for internalized insulin in rat hepatocytes that colocalized partially with CD. In vivo pepstatin A treatment was without any observable effect on the insulin receptor content of endosomes but augmented the phosphotyrosine content of the endosomal insulin receptor after insulin injection. These results suggest that CD is the endosomal acidic insulinase activity which catalyzes the rate-limiting step of the in vivo cleavage at the Phe(B24)-Phe(B25) bond, generating the inactive A(1--21)-B(1--24) insulin intermediate.
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PMID:Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D. 1177 65

Apolipoprotein E (ApoE) 4 is a potent risk factor for Alzheimer's disease (AD). However, the mechanism underlying ApoE4 function in the pathology of AD is not well understood. We report here that, in comparison with ApoE2 and ApoE3, ApoE4 significantly reduces levels of insulin-degrading enzyme (IDE), which is responsible for the cellular clearance of Abeta in neurons. This differential regulation of IDE by various ApoE isoforms was blocked by coincubation with N-methyl-d-aspartic acid (NMDA) receptor inhibitors and receptor-associated protein (RAP), which blocked the interaction between ApoE and members of the low-density lipoprotein (LDL) receptor family. Moreover, inhibition of the NMDA receptor increased IDE levels in neurons, while activation of the NMDA receptor-reduced IDE expression. Further studies demonstrate that, as a pathway downstream of the NMDA receptor, cAMP-dependent protein kinase (PKA) contributes to the NMDA receptor-reduced IDE expression. These results suggest that ApoE4 down-regulates IDE expression in neurons by binding to its receptor and stimulating the NMDA receptor pathway, which may account for its role in AD pathogenesis.
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PMID:ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. 1961 72

Insulin binding to insulin receptor (IR) at the cell surface results in the activation of IR kinase and initiates the translocation of insulin-IR complexes to clathrin-coated pits and to early endosomes containing internalized but still active receptors. In liver parenchyma, several mechanisms are involved in the regulation of endosomal IR tyrosine kinase activity. Two of these regulatory mechanisms are at the level of intraendosomal ligand. First, a progressive decrease in endosomal pH mediated by the vacuolar H(+)-ATPase proton pump promotes dissociation of the insulin-IR complex. Second, free dissociated insulin is degraded by a soluble endosomal acidic insulinase, which has been identified as aspartic acid protease cathepsin D. This enzyme catalyzes the cleavage of insulin at the Phe(B24)-Phe(B25) bond, generating a major clipped molecule, A(1-21)-B(1-24) insulin, that can no longer bind to IR within endosomes. Concomitant with, or shortly after, the tyrosine-phosphorylated IR is deactivated by two independent processes: its rapid dephosphorylation by endosome-associated phosphotyrosine phosphatase(s) and its association with the molecular adaptor Grb14, with resulting inhibition of IR catalytic activity. By mediating the removal and degradation of circulating insulin, as well as the deactivation of the activated IR, internalization of the insulin-receptor complex into endosomes represents a major mechanism involved in the negative regulation of insulin signaling.
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PMID:Assessment of insulin proteolysis in rat liver endosomes: its relationship to intracellular insulin signaling. 2437 14