Proteolysis

Protein degradation or proteolysis occurs in living organisms under normal and pathological conditions. This process is highly controlled by proteolytic enzymes. Cysteine peptidases as one of the four mechanistic classes of proteolytic enzymes are widely distributed in animals, plants and microorganisms. Among many families of cysteine peptidases the largest and best-known being the papain family, which is the object of the proposed programme. Until recently, information about these enzymes of mammalian origin, mostly human, has been limited only to lysosomal cathepsins B, H, L and S. Using a new molecular biology approach, currently more than 15 human cathepsins are known at the sequence level. Some of them are expressed in a variety of cells (cathepsins B, C, F, H, L, O and X), whereas others are tissue-specific (cathepsins S, K, V and W) and are involved in more specialized processes like antigen processing and presentation, in bone remodeling, and processing in various hormones and other proteins. They differ in their specificities, acting as endopeptidases, aminopeptidases and carboxypeptidases. The activities of cathepsins, are regulated mainly by zymogen activation and proteinase-inhibitor interactions. The determined crystal structures provide the basis for the understanding of the activation of cysteine peptidases. Propeptides are potent inhibitors of their corresponding enzymes. However, the main regulation of mature enzymes remains to be the inhibition by their endogenous protein inhibitors, the cystatins, and newly discovered thyroglobulin type-1 domain inhibitors, also called thyropins.