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 acidic glucagon-degrading activity of hepatic endosomes has been attributed to membrane-bound forms of cathepsins B and D. Endosomal lysates processed full-length nonradiolabeled glucagon to 32 different peptides that were identified by amino acid analysis and full-length sequencing. These indicated C-terminal carboxypeptidase, endopeptidase as well as N-terminal tripeptidyl-aminopeptidase activities in endosomes. Glucagon proteolysis was inhibited 95% by E-64 and pepstatin A, inhibitors of cathepsins B and D, respectively. This was confirmed by the pH 6-dependent chemical cross-linking of [125I]iodoglucagon to a polypeptide of 30 kDa, which was immunodepleted by polyclonal anti-cathepsin B antibody, and the removal of greater than 80% of glucagon-degrading activity by polyclonal antibodies to cathepsins B and D. By similar criteria, insulin-degrading enzyme was ruled out as a candidate enzyme for endosomal proteolysis of glucagon. Lysosomal contamination was unlikely since all forms of cathepsin B in endosomes, i.e. the major 45-kDa inactive precursor as well as the lesser amounts of the 32- and 28-kDa active forms, were tightly bound to endosomal membranes. Furthermore the mature 29-kDa single-chain and 22-kDa heavy-chain forms of cathepsin L were undetectable in endosomes, although high levels of the 37-kDa proform were observed. Membrane association of the cathepsins B and D was not to the mannose 6-phosphate receptor since association was unaffected by mannose 6-phosphate and/or EDTA, thereby indicating a distinct endosomal receptor. Hence, a pool of active cathepsins B and D as well as a poorly defined tripeptidyl aminopeptidase is maintained in endosomes by selective membrane retention. These hydrolases degrade glucagon internalized into liver parenchyma early in endocytosis.
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PMID:Proteolysis of glucagon within hepatic endosomes by membrane-associated cathepsins B and D. 779 82

Peptide ligands presented by MHC class I molecules are produced by intracellular proteolysis, which often involves multiple steps. Initial antigen degradation seems to rely almost invariably on the proteasome, although tripeptidyl peptidase II (TPP II) and insulin-degrading enzyme (IDE) may be able to substitute for the proteasome in rare cases. Recent evidence suggests that the net effect of cytosolic aminopeptidases is destruction of potential class I ligands, although a positive role in selected cases has been documented. This may apply particularly to the trimming of long precursors by TPP II. In contrast, trimming of ligand precursors in the endoplasmic reticulum is essential for the generation of suitable peptides and has a substantial impact on the repertoire of ligands presented. Trimming by the ER aminopeptidase (ERAP) enzymes most likely acts on free precursors and is adapted to the needs of class I molecules by way of a molecular ruler mechanism. Trimming by ERAP enzymes also occurs for cross-presented ligands, which can alternatively be processed in a special endosomal compartment by insulin-regulated aminopeptidase.
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PMID:Post-proteasomal and proteasome-independent generation of MHC class I ligands. 2139 May 45