ReviewCysteine proteases as disease markers
Introduction
This review comprises issues concerning human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The classification of cysteine proteases can be found in the MEROPS database [1], reviewed in Ref. [2]. Since these enzymes contain cysteine in their active site, and all of them are termed cathepsins, they can be called cysteine cathepsins (CCs) (to differentiate them from cathepsins belonging to serine or aspartate proteases, such as cathepsin G or cathepsin D, respectively). The classification of human cysteine cathepsins is shown in Table 1. The best known CCs, cathepsins B, L and H, are distributed ubiquitously in most tissues, where they catalyze protein hydrolysis within the lysosomes. Similar common expressions show cathepsins F, O, X and C, whereas cathepsins S, K, W and V are comprised to specific tissues (Table 2). Except for cathepsin C, all of the other CCs are monomers consisting of two domains, R (right) and L (left), which are formed in a V-shaped configuration. At the bottom of the V cleft, active site aminoacids; cysteine and histidine are situated [3]. Cysteine cathepsins are synthesized as 30–50 kDa preproenzymes, directed into lysosomes where they serve their function of protein hydrolysis. After signal peptides removal, the molecular mass of these enzymes remains within the range of around 20–35 kDa. Genes encoding CCs consist of about 10 exons separated by introns. Cathepsin C differs from the rest of these proteases both at the genetic and protein level. Its gene comprises only two exons and one intron. Also, the proteinaceous product of the gene expression is different in comparison with other enzymes; cathepsin C consists of four identical 50 kDa monomers and exhibits the ability of simultaneous joining four substrate molecules [4]. Another distinguished enzyme belonging to CCs is cathepsin W. Unlike other cathepsins, which in physiological conditions occur within lysosomes, it has been localized within the endoplasmic reticulum of natural killer cells [5].
Section snippets
Physiological role of cysteine cathepsins
Except for the well-known function of CCs within the lysosomes, consisting in protein degradation, various specific physiological roles have been ascribed to these enzymes. They are involved in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis.
Cancer
The information concerning participation of cysteine cathepsins in cancer diseases has been presented in several recent review papers. The possible role of CCs (especially cathepsin B) in cancer development has been discussed by Koblinski et al. [63] and Yan et al. [64], and the usefulness of these enzymes in diagnosis and prognosis has been analyzed by Kos et al. [65] and Lah and Kos [66]. Therefore, in the present paper the general involvement of CCs in cancer progression will be summarized
Concluding remarks
In the light of the available at present information, it could be assumed that in some disorders CCs can be applied as diagnostic and prognostic markers. However, even in the case of the best-studied cathepsins B and L, experimental data coming from multiple sources are often ambiguous. The discrepancies result from separate approaches to an experimental design, which includes differences in methodology (various assays determining an enzyme at mRNA, protein or activity level), patients
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