Lysosomes proteolytic digestion

Two ways of enhancing the toxicity of A chain ITs have been described. Firstly, the ITs frequently show a moderate to dramatic increase in potency in the presence of monensin [184,185], ammonium chloride [186,187] or chloroquine [188]. It seems likely that these reagents reduce the rate of proteolytic digestion of the ITs by elevating endosomal and lysosomal pH. Secondly, the addition of free B chain gives a markedly enhanced cytotoxic... 

Mammals, fungi, and higher plants produce a family of proteolytic enzymes known as aspartic proteases. These enzymes are active at acidic (or sometimes neutral) pH, and each possesses two aspartic acid residues at the active site. Aspartic proteases carry out a variety of functions (Table 16.3), including digestion pepsin and ehymosin), lysosomal protein degradation eathepsin D and E), and regulation of blood pressure renin is an aspartic protease involved in the production of an otensin, a hormone that stimulates smooth muscle contraction and reduces excretion of salts and fluid). The aspartic proteases display a variety of substrate specificities, but normally they are most active in the cleavage of peptide bonds between two hydrophobic amino acid residues. The preferred substrates of pepsin, for example, contain aromatic residues on both sides of the peptide bond to be cleaved. 

As shown in Table I, free HRP is poorly transported across MDCK cells but, when conjugated to a PLL carrier, HRP transport is increased considerably. The existence of a proteolytic compartment involved in the transcytotic digestion of HRP-S-PLL conjugate was further confirmed by the finding that when PLL was replaced by PDL, the transport of HRP was completely abolished (Table I) (8). In addition, when protease inhibitors such as leupeptin were added to the basal medium, the transcytosis of HRP was also significantly decreased (Table I). We have previously reported that the partial degradation of HRP-S-PLL was not inhibited by lysosomotropic amines (<8), indicating that this proteolytic process does not occur in lysosomes. 

The liver eliminates proteins on first pass after oral administration and on each pass of hepatic blood flow. Hepatocytes, Kupffer cells, adipocytes, and endothelial cells can all be involved in proteolysis (Figure 5.6). Proteolysis can occur in lysosomes after endocytosis of a protein and lysosomal fusion. Endocytosis of a protein may be a nonspecific or receptor-mediated process. Proteolytic products are eliminated from the liver through biliary excretion, and subsequently digested further in the intestinal tract. 

In the case of soluble lysosomal enzymes, the proproteins are called proenzymes, which are sorted by the M6P receptor as catalytically Inactive enzymes. In the late endosome or lysosome a proenzyme undergoes a proteolytic cleavage that generates a smaller but enzymatically active polypeptide. Delaying the activation of lysosomal proenzymes until they reach the lysosome prevents them from digesting macromoT ecules In earlier compartments of the secretory pathway. 

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