Cathepsin Cations

CAH Chronic active hepatitis CALLA Common lymphoblastic leukaemia antigen CALX Conjunctival associated lymphoid tissue CaM Calmodulin cAMP Cyclic adenosine monophosphate also knomt as adenosine 3, 5 -phosphate CAM CeU adhesion molecule CAP57 Cationic protein from neutrophils CAT Catalase CatG Cathepsin G... 

Cathepsin G, a cationic, glycosylated protein of relative molecular mass -27 kDa, exists in four isoforms (25-29 kDa) that are identical in amino acid sequence but differ in levels of glycosylation. It is a component of azurophilic granules and present in human neutrophils at 1.5-3 jug/106 cells, but at lower levels in monocytes. cDNA has been cloned and sequenced (and the amino acid sequence predicted), and the gene has been localised to chromosome 14ql 1.2. The gene comprises five exons and four introns, a structure similar to that of the elastase gene. 

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)... 

Molecules which can break down or permeabi-lize microbial membranes and thereby mediate extracellular killing of microorganisms, e.g. enzymes (lysozyme or cathepsin G), bactericidal reactive oxygen species and cationic proteins. 

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]. 

Whereas the acyl dipeptide substrates of pepsin were resistant to acid proteinases such as cathepsin D (25,26), several of the more sensitive cationic substrates were cleaved by these and other members of this family of proteinases (27,28). The apparent differences in the specificity of the action of these enzymes have been shown to be a consequence, in large part, of the contribution made by secondary enzyme-substrate interactions to catalysis (29). 

In all the replacement reactions catalyzed by cathepsin and papain studied by Fruton and his collaborators the optimum pH of the replacement reaction was at 7-8, whereas that of hydrolysis is near to 5. The authors suggest that at normal physiological pH values the catalysis of replacement may represent a major intracellular function of cathepsins and papainases. But what measurements there are of intracellular pH in mammalian kidney, liver, and muscle indicate it to be nearer 6 than 7 (49,51,98). The pH dependence in these transfer reactions is related to the pK of the cation of the replacement agent. 

Additional serine proteases have been found in chronic wounds and neutrophils probably are also the primary source of these enzymes. These include cathepsin G, another cationic serine protease with broad substrate specificity, urokinase-type plasminogen activator (itfA), and protease 3 (3,32-35). In all probability, when looked for, elevated levels of additional neutrophil proteases will be found in chronic dermal ulcers. 

---