Cathepsin C and

This enzyme [EC 3.4.14.1], also called cathepsin C and cathepsin J, catalyzes the hydrolysis of a peptide bond resulting in the release of an N-terminal dipeptide, XaaXbb-Xcc, except when Xaa is an arginyl or a lysyl residue, or Xbb or Xcc is a prolyl residue. This enzyme, a member of the peptidase family Cl, is a CF-dependent lysosomal cysteine-type peptidase. 

Liver flukes also possess cathepsin C and LAP exopeptidases that are orthologous to the schistosome enzymes. These exopeptidases most likely complete the digestive process to yield free dipeptides and amino acids, respectively, from peptides generated by endoprote-olytic cysteine protease activity on host proteins. Both cathepsin C and LAP have been immunolocalized to gastrodermal cells (Carmona et al., 1994 Acosta et al., 1998 J.P. Dalton, unpublished data). 

Other syntheses were performed including one in which the action of cathepsin C and papain were coupled. It should be noted that papain exhibits stereochemical specificity toward the substrate but apparently not toward the replacing agent in these reactions. Fruton and his associates (61-63,95-97) have shown that chymotrypsin, cathepsin C, and trypsin can also catalyze transpeptidation reactions. 

Falcone, F., Tetteh, K.K.A., Hunt, P., Blaxter, M.L., Loukas, A.C. and Maizels, R.M. (2000) The new subfamily of cathepsin Z-like protease genes includes Tc-cpz-1, a cysteine protease gene expressed in Toxocara canis adults and infective larvae. Experimental Parasitology 94, 201-203. 

Lewis, T., Hartmann, C. B., and McCoy, K. L., Gallium Arsenide Modulates Proteolytic Cathepsin Activities and Antigen Processing by Macrophages, J. Immunol., 161, 2151, 1998. 

Figure 7. Two examples of irreversible inactivators that are not suicide substrates a) TPCK, a classic" affinity label of the serine protease chymotrypsin, b) ZFK-CH2-mesitoate, a quiescent" affinity label of the cysteine protease cathepsin B, and c) the kinetic scheme for both forms of affinity label-inactivation.

Bl 1. Briozzo, P., Morisset, M., Capony, F., Rougeot, C., and Rochefort, H., In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. Cancer Res. 48, 3688-3692 (1988). 

G. M. Dubowchik, K. Mosure, J. O. Knype, R. A. Firestone, Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Pachtaxel, Mitomycin C and Doxorubicin , Bioorg. Med. Chem. Lett. 1998, 8, 3347-3352. 

The cytosolic targets of cathepsin D have not been ascertained. However, since we found that inhibition of cathepsin D prevented both release of cytochrome c and activation of caspase-3-like caspases, we suggest that cathepsin D exerts its effect upstream of both the release of cytochrome c from mitochondria and the onset of the caspase cascade. Cathepsin B seems to be of minor importance in this system, because we observed that the activity of cathepsin B decreased and the cathepsin B inhibitor CA074-Me had no influence on the rate of apoptosis (Kagedal et al 2001). 

Roberg, K., 2001, Relocalization ofcathepsin D and cytochrome c early in apoptosis revealed by immunoelectron microscopy. Lab. Invest. 81 149-158 Roberg, K., Johansson, U., and OUinger, K., 1999, Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress. Free Radio. Biol. Med. 27 1228-1237 Roberg, K. and OUinger, K., 1998, Oxidative stress causes relocation of the lysosomal... 

Gowen, M., Lazner, F., Dodds, R., Kapadia, R., Felid, J., Tavaria, M., Bertoncello, L, Drake, F., Zavarselk, S., Tillis, L, Hertzog, P., Debouck, C., and Kola, I. (1999) Cathepsin K Knockout Mice Develop Osteopetrosis Due to a Deficit in Matrix Degradation but not Deminerali zation. Journal of Bone and Mineral Research 14, 1654-63. 

In aminoglycoside-treated animals, the cells can be led to canonical apop-totic death through activation of caspases. Caspase-9 forms an apoptosome complex with cytochrome c and APAF-1 and leads to apoptosis through activation of caspase-3. Aminoglycosides activate caspases in auditory structures conversely, inhibition of caspase activity successfully blocks neomycin-induced vestibulotoxicity. In contrast, apoptotic markers were essentially absent in a mouse model of chronic kanamycin ototoxicity where death of auditory sensory cells ensued via cathepsins. The activation of cathepsin D was accompanied by the nuclear translocation of endonuclease G, necrotic cleavage of PARP, and activation of p,-calpain, all facets of necrotic cell death. 

Antiviral 2,5-disubstituted imidazo[4,5-f]pyridines have been reported for the treatment of hepatitis C <2007BML390, 2007BML5111>. A method for the preparation of substituted l//-imidazo[4,5-f]pyridines as immune response modifiers has been reported <2007W0092641>. 6-Phenyl-l//-imidazo[4,5-f]pyridine-4-carbo-nitrile derivatives have been reported to act as cathepsin K and S inhibitors <2007USP179138>. Imidazo[4,5-4pyridine derivatives have also been prepared as C3A receptor antagonists <2007W0034277>. 

Most of the lysosomal proteases called cathepsins are small 20- to 40-kDa glycoproteins found in all animal tissues.313 Most are cysteine proteases which function best and are most stable in the low pH reducing environment of lysosomes. They resemble papain in size, amino acid sequence, and active site structures. Papain is nonspecific but most cathepsins have definite substrate preferences. Cathepsin B is the most abundant. There are smaller amounts of related cathepsins H (an aminopeptidase)314 and L315 and still less of cathepsins C, K, and others. Cathepsin B is both an endopep-tidase and an exopeptidase.316 It acts on peptides with arginine at either Pj or P2 but also accepts bulky hydro-phobic residues in Pj and prefers tyrosine at P3.317 Cathepsin S is less stable at higher pH than other cathepsins and has a more limited tissue distribution, being especially active in the immune system.318 319... 

Final degradation of substrates to oligopeptides and free amino acids may involve gastro-dermal exopeptidases such as a cathepsin C (Caffrey et al., 2004), which removes dipeptides from the N-terminus of proteins, and a leucine aminopeptidase (LAP McCarthy et al., 2004), which is capable of releasing free amino acids from peptides and dipeptides. However, it is notable that cathepsin B also exhibits carboxydipeptidase activity and, therefore, may well play a dual role (Tort et al., 1999 Caffrey et al., 2004). 

Brady, C.P., Brindley, P.J., Dowd, A.J. and Dalton, J.P. (2000a) Schistosoma mansoni differential expression of cathepsin L1 and cathepsin L2 suggests discrete biological functions for each enzyme. Experimental Parasitology 94, 75-83. 

Skelly, P.J. and Shoemaker, C.B. (2001) Schistosoma mansoni proteases Sm31 (cathepsin B) and Sm32 (legu-main) are expressed in the cecum and protonephridia of cercariae. Journal of Parasitology 87, 1218-1221. 

---