Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors.
Cysteine proteinases are widely distributed among living organisms. According 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 the most abundant among the cysteine proteinases. The family consists of papain and related plant proteinases such as chymopapain, caricain, bromelain, actinidin, ficin, and aleurain, and the lysosomal cathepsins B, H, L, S, C and K. Most of these enzymes are relatively small proteins with Mr values in the range 20000-35000 (reviewed in Brocklehurst et al., 1987; Polgar, 1989; Rawlings and Barrett, 1994; Berti and Storer, 1995), with the exception of cathepsin C, which is an oligomeric enzyme with Mr approximately 200000 (Metrione et al., 1970; Dolenc 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 animals, 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 et al., 1995), although cathepsin B was found also to be a dipeptidyl carboxypeptidase (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, cathepsin L was found to be the most active in degradation of protein substrates, such as collagen, elastin and azocasein (Barrett and Kirschke, 1981; Maciewicz et al., 1987; Mason et al., 1989), arid cathepsin B the most abundant (Kirschke and Barrett, 1981). All the enzymes are optimally active at slightly acidic pH, although their pH optima for degradation of synthetic substrates vary from 5.5 for cathepsin L to 6.8 for cathepsin H (reviewed in Kirschke et al., 1995). Several other lysosomal cysteine proteinases, such as cathepsins N, T and K, are known, although their properties are less well characterised (reviewed in Kirschke 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 osteoclasts (Drake et al., 1996) with properties similar to cathepsin L (Bossard et al., 1996).
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Department of Biochemistry and Molecular Biology, J. Stefan Institute, Ljubljana, Slovenia.
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D000818:Animals; D015891:Cystatins / Q000737:chemistry / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases; D010206:Papain