Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibrin(ogen) is important for hemostasis and is cleared from sites of vascular injury primarily by the plasminogen activator system. However, there is emerging evidence in plasminogen activator-deficient transgenic mice that non-plasmin pathways may also be important for endogenous fibrinolysis. We have recently described an alternative, plasmin-independent fibrinolytic pathway in activated human monocytes that utilizes the integrin Mac-1 (CD11b/CD18), which directly binds and internalizes fibrin, resulting in its lysosomal degradation. The identity of the lysosomal fibrinolytic enzyme(s) responsible for monocyte/macrophage-mediated fibrinolytic is unknown. Protease inhibitor studies now suggest that an aspartyl protease is responsible for this fibrinolytic activity. We, therefore, examined the fibrinolytic properties of cathepsin D, a lysosomal aspartyl protease, and report that cathepsin D possesses both fibrinogenolytic and fibrinolytic activity. Cathepsin D cleavage of fibrinogen follows Michaelis-Menten kinetics with a Michaelis constant, Km, of 1.5 microM; catalytic rate constant, kcat, of 1.4 x 10(-3) s-1; and catalytic efficiency, kcat/Km, of 9.3 x 10(-4) microM-1 s-1. A pH-activity profile of fibrinogen digestion by cathepsin D demonstrates a pH optimum of 3.5 with 50% residual activity at pH 5.0. Fibrinolysis was assessed by fibrin plate and fibrin clot lysis assays. Cathepsin D possesses significant fibrinolytic activity over a dose range of 100 nM to 10 microM and is able to lyse fibrin, as well as albumin-enriched and albumin/red cell-enriched fibrin clots. Cathepsin D cleaves the alpha-, beta-, and gamma-chains of FGN, generating multiple low-molecular-weight fragments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The fibrin(ogen)olytic properties of cathepsin D. 820 91

The monocyte/macrophage plays a central role in fibrinolysis. Cell-surface of components of the plasminogen activator system leads to the elaboration of plasmin, which facilitates degradation of fibrin in the pericellular environment, as well as activation of matrixins, which promote degradation of matrix components. Fibrin degradation also occurs by way of a proteolytic system within the macrophage lysosome that does not involve plasmin. This alternate pathway involves first the binding of fibrin(ogen) to the surface integrin Mac-1 (CD11b/CD18) followed by internalization of the complex into the lysosome where the aspartyl protease cathepsin D degrades the protein. These molecular events underlie the many physiologic and pathophysiologic processes in which the monocyte/macrophage is involved, including adhesion, migration, matrix degradation and remodeling, wound healing, fibrinolysis, and atherosclerosis.
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PMID:The macrophage and fibrinolysis. 912 15