Cathepsins serine proteinases

Chymotrypsin-like proteinases are serine proteinases that recognize pqDtide residues with aromatic side chains (phyenylalanyl or tyrosyl residues) and that effect hydrolysis of the polypeptide chain on the carboxy-terminal side of these residues. Examples of chymotrypsin-like proteinases are chymotrypsin and cathepsin-G. 

Mitsudo K, Jayakumar A, Henderson Y, et al. Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI A kinetic analysis. Biochemistry 2003 42 3874-3881. 

Optimization of the peptide backbone of these aldehydes to take advantage of the binding interactions in the 8,-84 subsites afforded potent inhibitors of HLE, for example, aldehyde (6-6) [124]. Concurrent with the increases in potency, the selectivity of these compounds also improved. For example, aldehyde (6-5) was inactive at 100 //M against other enzymes, including the serine proteinases trypsin, chymotrypsin, and cathepsin G [125]. Aldehyde (6-5) was compared with a,-PI and was shown to be more potent in vitro (on a weight basis) and more stable towards oxidative inactivation by cigarette smoke [128]. 

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)... 

Neutral proteinases, elastase (EC 3.4.21.11), cathepsin G, and a third serine proteinase seem to be the most important mediators of these effects. In addition to their degradative properties, it was found that PMN elastase and cathepsin G can stimulate lymphocyte B antibody formation in vitro (VI). The granules have been intensively studied for their role in the oxidative burst of the PMN this aspect is discussed in Section 4.4. 

Defensins, small cysteine-rich cationic proteins, and cathepsin G, a neutral serine proteinase (both stored in the azurophil granules of neutrophils), are now seen as important immune regulatory tools [15, 16]. 

Nevertheless, proteinase inhibitors may therefore be useful as therapeutic agents in anti-invasive and anti-metastatic treatment. Studies have shown that potato cysteine proteinase inhibitor PCPI 8.7 inhibited invasion B16 mouse melanoma cell by 21% and serine proteinase inhibitor reduced invasiveness by up to 24 % (Sever et al., 2005). Overexpression of cathepsin B excessively associated with adenocarcinoma of the esophagus and other cancers (Kos Lah, 1998). 

Cathepsins are intracellular proteinases that reside within lysosomes or specific intracellular granules. Cathepsins are used to degrade proteins or pqffides that are internalised from the extracellular space. Some cathepsins such as cathepsin-G or cathepsin-K may be released from the cell to degrade specific extracellular matrix proteins. All cathepsins except cathepsin-G (serine) and cathepsin-D (aspartyl) are cysteine proteinases. 

Serine proteases, released from immune cell granules, process cytokines and growth factors that control multiple cellular process [56], Proteinase 3, cathepsin G, and elastase all cleave membrane-bound TNF-o, IL-1, and IL-18, and activate epidermal growth factor receptor (EGFR) and toll-like receptor-4 (TLR-4). These actions inhibit growth and lead to apoptosis with transcriptional nuclear factor kB (NF-kB) inactivation. Bik suppresses release of TNF-o, IL-1, and IL-18 and prevents EGFR and TLR-4 activation. Activation of NF-kB is a mediator of cell proliferation, whereas inhibition of NF-/. B leads to apoptosis [82]. Overall, Bik inhibition of immune cell serine proteases increases cell proliferation and stability. 

INHIBITORS - The search for new agents which modify the rheumatic process has recently been oriented toward finding inhibitors of the enzymes directly involved in joint destruction. These Include inhibitors of the serine (elastase, cathepsin G, plasminogen activator) and metallo (collagenase, non-collagenolytic) proteinases. These compounds have been derived from both natural and synthetic sources. 

Dozens of different peptides have been identified in cheeses. Most of them arise from and -caseins and a few are from aj2-and K-caseins. The proteinases involved in hydrolysis of aj -casein are mainly cathepsin D originating from milk and cell-envelope proteinase from thermophilic starters, while P- and aj2-caseins are mainly hydrolysed by plasmin. Moreover, peptidases from starters are also active throughout the ripening process, presumably similar to those from non-starter lactic acid bacteria. For example, the bitterness of mature Gouda cheese is caused by calcium and magnesium chlorides, some bitter-tasting free amino acids and is modified by peptides, which arise from the hydrolysis of fS-casein (such as decapeptide Tyr-Pro-Phe-Pro-Gly-Pro-Ile-His-Asn-Ser and derived nonanpeptide without the terminal serine) and casein (tetrapeptide Leu-Pro-Gln-Glu). 

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