Lysosomal cathepsins

E2. Eekhout, Y., and Vaes, G., Further studies on the activation of procollagenase, the latest precursor of bone collagenase Effects of lysosomal cathepsin B. plasmin and kallikrein and spontaneous activation. Biochem. J. 36, 1555-1563 (1977). 

Morales, M.E., Kalinna, B.H., Heyers, O., Schulmeister, A., Mann, V.H., Copeland, C.S. Loukas, A. and Brindley, P.J. (2004) Genomic organization of the Schistosoma mansoni aspartic protease gene, a platy-helminth orthologue of mammalian lysosomal cathepsin D. Gene 338, 99-109. 

Cysteine proteases are so called because of a critical cysteine involved (together with an adjacent histidine) in the catalytic mechanism. Cysteine proteases include papain-related proteases, calpain-related proteases and the caspases. Papain-like cysteine proteases include the plant enzymes actinidin, aleurain, bromelain, caricain, chymopapain, ficin and papain and the lysosomal cathepsins B, C, H, K, L and S. Cathepsin C is multimeric (MW -200,000), but the other papain-related proteases are monomeric with MWs of about 20,000-35,000. While cathepsin C is a dipeptidyl aminopeptidase, the other enzymes are endopeptidases. Cathepsin B is an endopeptidase and a dipeptidyl carboxypeptidase. Cathepsin H is an endopeptidase and an aminopeptidase. In higher animals, cathepsin B generates peptides from antigens for presentation to T cells by the major histocompatibility... 

Inhibitor (PCPI) (20 kDa) (Solanaceae) [tuber] homologue) - lysosomal cathepsin L (70pM)... 

Bechet DM, Ferrara MJ, Mordier SB, Roux MP, Deval CD, Obled A. Expression of lysosomal cathepsin B during calf myoblast-myotube differentiation, characterization of a cDNA encoding bovine cathepsin B. J Biol Chem. 1991 266 14104-14112. 

In cysteine proteinases (CP), activity depends upon a cysteine thiol group. Papain, actinidin, and a few lysosomal cathepsins are the best known members of this family. They hydrolyze peptides and esters in a generally similar fashion to serine proteinases. Two residues are directly involved in the catalytic process, Cys and His, with apparent pKa values of 4.2 and 8.6, respectively. This is the reverse of their normal pKa order, with His being more acidic than Cys. A bell-shaped relation of activity vs. pH for papain is spread out, with maximal activity around pH=6.5 and about half of the activity is retained near 4.5 and 8.5, dropping fast below and above these values. Thus, the active species has a zwitterion state, with a cysteine anion (thiolate) and a histidine cation. CP were discussed in a few reviews (Baker and Drenth, 1987 Fersht, 1985 Polgar and Halasz, 1982)... 

Despite considerable research, the mechanisms of protein turnover are still unclear. However, several aspects of this process are now known. Proteins are degraded by proteolytic enzymes found throughout the cell. These include the cytoplasmic Ca2+-acti-vated calpains and the lysosomal cathepsins. In addition, ubiquina-tion is now believed to have a major role in protein turnover. In ubiquination, illustrated in Figure 15A, several molecules of a small 76-residue eukaryotic protein called ubiquitin are covalently attached to some proteins destined for degradation. Once a pro-... 

The importance of muscle lysosomal enzymes to the food scientist stems from their apparent involvement in the aging of meats. For example, lysosomal cathepsins are possibly involved in the proteolytic degradation of muscle proteins (31). Lysosomal enzymes exhibit latency that is, they are retained in the lysosomal particle and released only when the particle membrane is damaged. In this regard the lysosomal enzymes are liberated and activated when the particle membranes are weakened by the postmortem drop in pH. Also, lysosomes are very subject to cryoinjury (72), and freezing and thawing of tissues such as muscle releases lysosomal enzymes resulting in autolysis. 

K. Worowski, Lactacystin, a specific inhibitor of the proteasome, inhibits human platelet lysosomal cathepsin A-like enzyme, Biochem. Biophys. Res. Commun. 1997, 234, 729-732. 

When leupeptin and E-64 were injected in vivo, the activity of cathepsin B and L in the lysosomal fraction of liver was inhibited within 1 hour and the inhibition persisted for at leeist 6 hours, but gradually disappeared within 36 hours (64) (Fig. 4). There was no difference in the time courses of inhibition by most derivatives of E-64 and leupeptin tested, but some derivatives of E-64 were ineffective in vivo, although they inhibited cathepsin B and L in vitro. Inhibition of cathepsin B and L by injection of leupeptin or E-64 was as marked in the kidney as in the liver, but these compoimds were less effective in skeletal muscle and heart. Hashida et al. (72) showed that E-64 administered in vivo penetrates into lysosomes of the liver, possibly by permeation rather than by endocytosis. When H-labeled E-64 was injected into rats ip, high levels of radioactivity were observed in the serum after a short time and later in the cytosol fraction of liver. While radioactivity in the serum had already decreased 1 hour after the injection, that in the lysosomal fraction increased to a maximum after 6 hours and then gradually decreased (Fig. 5). E-64 was mostly present in the free form in the blood and the c3ftosol fraction but in protein-bound form in the lysosomal fraction. The time course and dose-response of inhibition of lysosomal cathepsin B activity by E-64 was closely correlated with the radioactivity in the protein-bound fraction of the lysosomes. 

In addition to activated macroautophagy, our studies provided important evidence that autophagy related to lysosomal function is impaired in s-IBM muscle fibers. They showed a decrease of lysosomal cathepsin D and B enzymatic activities that appeared spedfic to s-IBM, because in polymyositis muscle fibers their activities were actually increased in our study [13] and in studies by others (referenced in [13]). In polymyositis macroautophagy was also increased but autophagic vacuoles and indusions do not form, perhaps because the lysosomal system may be functioning adequately. Our results also suggest that lymphocytic inflammation, which is... 

In the muscle, there are lysosomal cathepsins B, D, H and L, which are most active in acidic pH, sarcoplasmic m- and m-calpains, which are activated by Ca and exhibit most activities in neutral pH, and a proteasome dependent on ATP for activation. 

Inactivation of Rabbit Liver and Muscle Aldolases by Limited Proteolysis by Lysosomal Cathepsin M... 

Figure 2. Structure of human thyro-globulin and its degradation in thyroid lysosomes. A single thyroglobulin molecule is depicted schematically with positions of its iV-linked oligosaccharides [41] , complex o high-mannose , complex or high-mannose , hybrid or complex. Tyrosines Y5 and Y130 are the major residues involved in the formation of hormones T4 and T3 [1]. Principal sites of proteolytic cleavage by lysosomal cathepsins B, D, and L are shown as vertical lines [3],...

Another example of a genetic mutation in a lysosomal cathepsin that causes a specific human disorder has recently come to light [43]. The disease is pycnodysos-tosis which is an autosomal recessive skeletal dysplasia. Clinical features of pycno-dysostosis were first described in 1962 by Maroteaux and Lamy [60] to include bone fragility, dental abnormalities, reduced stature and skull deformities with a delay in closure of the cranial sutures. The disease experienced considerable acclaim due to the initial prediction by Maroteaux and Lamy, recently refuted [61], that this was the genetic disorder suffered by the famous French impressionist artist Toulouse-... 

Many authors have investigated the influence of ozone on pulmonary lysosomes and mitochondria. Lysosomes contain quite many enzymes, mainly hydrolases, such as protease, lipases, nucleases, phosphatases, phosphodiesterases, etc. Dillar et al. [273] have studied the changes in lysosome levels upon exposure of mice to ozone (0.7 ppm). The activity of pulmonary lysosomal cathepsin A, cathepsin D, acidic phosphatase, (3-N-acetylglucose aminidase, and benzyl arginine P-naphthylamide ami-dohydrolase was increased. This is due to inflammatory processes caused by ozone. The specific activity of protease and peptidase in the lung is enhanced when related to chronic obstructive genetic lack of a-1-antitrypsin factor. 

Cathepsins are proteases mainly present in lysosomes cathepsin E is an aspartyl protease that intervenes in gastric cancers. Cathepsins A and G are serine proteases. 

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