STRUCTURAL AND FUNCTIONAL-ASPECTS OF PAPAIN-LIKE CYSTEINE PROTEINASESAND THEIR PROTEIN INHIBITORS

Cysteine proteinases are widely distributed among living organisms. Ac cording to the most recent classifications (Rawlings and Barrett, 1993 , 1994), they can be subdivided on the basis of sequence homology into 14 or even 20 different families, the most important being the papain and the calpain families. The papain-like cysteine proteinases are th e most abundant among the cysteine proteinases. The family consists of papain and related plant proteinases such as chymopapain, caricain, b romelain, actinidin, ficin, and aleurain, and the lysosomal cathepsins B, H, L, S, C and K. Most of these enzymes are relatively small prote ins with M, values in the range 20000 - 35000 (reviewed in Brocklehurs t et al., 1987; Polgar, 1989; Rawlings and Barrett, 1994; Berti and St orer, 1995), with the exception of cathepsin C, which is an oligomeric enzyme with M, -200000 (Metrione et al., 1970; Doleno et al., 1995). A number of cysteine proteinases are located within lysosomes. Four of them, cathepsins B, C, H and L, are ubiquitous in lysosomes of animal s, whereas cathepsin S has a more restricted localisation (Barrett and Kirschke, 1981; Kirschke and Wiederanders, 1994). The enzymes, except cathepsin C, are endopeptidases (reviewed in Kirschke ef al., 1995), although cathepsin B was found also to be a dipeptidyl carboxypeptidas e (Aronson and Barrett, 1978) and cathepsin H also an aminopeptidase ( Koga et al., 1992). Cathepsin C is a dipeptidyl aminopeptidase, but at higher pH it exhibits also dipeptidyl transferase activity (reviewed in Kirschke et al., 1995). Among the lysosomal cysteine proteinases, c athepsin L was found to be the most active in degradation of protein s ubstrates, such as collagen, elastin and azocasein (Barrett and Kirsch ke, 1981; Maciewicz at al., 1987; Mason ef al., 1989), and cathepsin B the most abundant (Kirschke and Barrett, 1981). All the enzymes are o ptimally active at slightly acidic pH, although their pH optima for de gradation of synthetic substrates vary from 5.5 for cathepsin L to 6.8 for cathepsin H (reviewed in Kirschke et al., 1995). Several other ly sosomal cysteine proteinases, such as cathepsins N, T and K, are known , although their properties are less well characterised (reviewed in K irschke et al., 1995). In particular cathepsin K has attracted recent interest (Bromme et al., 1996; Shi et al., 1995; Bossard et al., 1996; Drake et al., 1996) and was found to be expressed specifically in ost eoclasts (Drake et al., 1996) with properties similar to cathepsin L ( Bossard et al., 1996).