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PubMed1985

A general framework of cysteine-proteinase mechanism deduced from studies on enzymes with structurally different analogous catalytic-site residues Asp-158 and -161 (papain and actinidin), Gly-196 (cathepsin B) and Asn-165 (cathepsin H). Kinetic studies up to pH 8 of the hydrolysis of N-alpha-benzyloxycarbonyl-L-arginyl-L-arginine 2-naphthylamide catalysed by cathepsin B and of L-arginine 2-naphthylamide catalysed by cathepsin H.

The pH-dependences of kcat, Km and kcat./Km for the hydrolysis at 25 degrees C at I 0.1 of L-arginine 2-naphthylamide catalysed by cathepsin H from bovine spleen were determined in the pH range approx. 4-8. The pH-dependences of these kinetic parameters were determined also for the hydrolysis at 25 degrees C at I 0.1 of N-alpha-benzyloxycarbonyl-L-arginyl-L-arginine 2-naphthylamide catalysed by cathepsin B (EC 3.4.22.1) from bovine spleen in the pH range 7-8, which extends the studies in acidic media reported by Willenbrock & Brocklehurst [(1984) Biochem. J. 222, 805-814]. These results are discussed and related to those from the reactivity-probe kinetics reported in the preceding paper [Willenbrock & Brocklehurst (1985) Biochem. J. 227, 511-519] and to known structural features present in rat liver cathepsins B and H and in papain (EC 3.4.22.2) and actinidin (EC 3.4.22.14). Consideration of the kinetic data leads to the suggestion that in the cysteine proteinases rearrangement of intimate S-/ImH+ ion-pairs in catalytic sites is brought about by a combination of field effects in the immediate vicinity of the ion-pair and consequences of protonic dissociation of a group with pKa 5-6 remote from the catalytic site. The contributions of the two types of effect seem to differ from enzyme to enzyme. Of the four cysteine proteinases considered, only cathepsin B exerts an absolute requirement for the proton-deficient form of a group with pKa 5-6 for catalytic activity. Protonic dissociation with pKa 5-6 enhances catalytic activity in cathepsin H and in actinidin and appears to have little or no effect in papain. Only cathepsin B lacks a polar or negatively charged side chain in the residue analogous to Asp-158 in papain, and this is suggested to account for its total dependence on a protonic dissociation remote from the catalytic site.

Arginine↗
PubMed1994

Engineering the S2 subsite specificity of human cathepsin S to a cathepsin L- and cathepsin B-like specificity.

The primary specificity of papain-like proteinases is largely determined by S2-P2 site interactions. According to the three-dimensional structure of a papain-inhibitor complex, the S2 subsite is defined by residues 67, 68, 133, 157, 160, and 205, with residues 133, 157, and 205 integrated into the wall and bottom of the side chain binding cavity. The S2 binding site specificity of this enzyme has been altered to mimic that of cathepsin B or L by the application of site-directed mutagenesis at these latter three positions in the cathepsin S sequence. The replacement of Gly-133 in cathepsin S by an alanine residue that is normally found at this position in both cathepsin B and L results in a pattern of specificity toward hydrophobic residues in P2 that is very similar to that of cathepsin B and L. The replacement of other cathepsin S S2 subsite residues with their cathepsin L equivalents (mutants Val-157-->Leu, Phe-205-->Ala) does not significantly change the specificity of cathepsin S. Cathepsin B is distinguished from both cathepsin L and S by its ability to efficiently hydrolyze substrates containing a basic P2 residue. A single mutation in position 205 of cathepsin S (Phe-205-->Glu) results in a change of specificity toward that of cathepsin B, i.e. the second-order rate constant for the hydrolysis of the cathepsin B-specific substrate benzyloxycarbonyl-Arg-Arg-4-methyl-7-coumaryl-amide is increased 77-fold for this mutant compared with the wild-type enzyme. A cathepsin S double mutant Gly-133-->Ala/Phe-205-->Glu is characterized by somewhat improved kinetic parameters compared with the Phe-205-->Glu single mutant. The hydrolysis rate of the benzyloxy-carbonyl-Arg-Arg-4-methyl-7-coumarylamide substrate by this double mutant is 130-fold higher than that of the wild-type enzyme. As with cathepsin B, the activities of the Phe-205-->Glu single and the Gly-133-->Ala/Phen-205-->Glu double mutants of cathepsin S toward the dibasic substrate is modulated by an additional ionizable group with a pKa of 5.7.

Alanine↗
PubMed1991

Collagenolytic cysteine proteinases of bone tissue. Cathepsin B, (pro)cathepsin L and a cathepsin L-like 70 kDa proteinase.

The aim of the work was to identify and characterize the cysteine proteinases of bone tissue, as these enzymes appear necessary for bone resorption. Three cysteine-dependent proteolytic activities were separated from a homogenate of mouse calvaria by a fractionation procedure involving (NH4)2SO4 precipitation, gel filtration and ion-exchange chromatography. The first two are typical cathepsins B and L with respect to (1) their reactivity with anti-(cathepsin B) and anti-(cathepsin L) antibodies respectively, (2) their relative rate constants for inhibition by benzyloxycarbonyl-Phe-Phe-CHN2 and L-3-carboxy-trans-2,3-epoxypropionyl-L-leucylamido-(4-guanid ino)butane and (3) their enzymic properties, such as the higher activities of cathepsin L against collagen and gelatin as compared with cathepsin B, and the fact that benzyloxycarbonyl-Arg-Arg 4-methoxy-2-naphthylamide is hydrolysed only by cathepsin B. Cathepsin L was mainly recovered in its precursor form, as indicated by its apparent 40 kDa molecular mass and its relative stability at pH 7.2. The third enzyme is a cathepsin L-like proteinase with an apparent molecular mass of 70 kDa. It is immunoprecipitated by anti-(cathepsin L) antibodies, and appears as the 25 kDa band of mature cathepsin L in Western blots. It further resembles (pro)cathepsin L with regard to its activities against synthetic substrates and proteins such as collagen, and with regard to its response to various inhibitors. However, unlike (pro)cathepsin L, it is eluted as a 70 kDa protein on gel filtration (even in the presence of 1% Brij or 1 M-NaCl), it is stable at pH values as high as 9, and it exhibits stronger affinity for phenyl-Sepharose. It might thus result from a strong complex between mature cathepsin L and another entity that confers stability at alkaline pH and favours hydrophobic interactions. This 70 kDa activity was also detected in mouse muscle and long bones of Ca(2+)-deficient chicks but not in mouse liver, spleen or kidney.

Animals↗
PubMed2001

Anti-cathepsin L monoclonal antibodies that distinguish cathepsin L from cathepsin V.

Cathepsin L is a lysosomal cysteine protease involved in intracellular protein degradation. Recently, several new cysteine proteases have been identified. Human cathepsin V, a thymus- and testis-specific human cysteine protease, shares 78% sequence identity with human cathepsin L. Due to the strong sequence similarity, highly selective reagents are needed to elucidate the physiological functions of the two enzymes. Monoclonal antibodies (mAbs) have been prepared against recombinant human cathepsin L. Antibodies produced by five clones reacted with procathepsin L and mature cathepsin L. They also reacted with cathepsin L in complex with a peptide fragment, which is identical to the alternatively spliced segment of the p41 form of MHC Class II associated invariant chain. Two mAbs, (M105 and H102) were specific for cathepsin L, while three (N135, B145 and D24) cross-reacted with cathepsin V. None of the mAbs cross-reacted with cathepsins B, H and S. We have developed a sandwich enzyme-linked immunosorbent assay (ELISA) for quantifying cathepsin L. This sandwich ELISA uses a combination of two monoclonal antibodies which recognize different, non-overlapping epitopes on the cathepsin L molecule. The lower detection limit of the sandwich ELISA was 5 ng of cathepsin L per ml.

Antibodies, Monoclonal↗
PubMed1987

Cathepsin E from rat neutrophils: its properties and possible relations to cathepsin D-like and cathepsin E-like acid proteinases.

An extract of rat neutrophils was found to contain a high hemoglobin-hydrolyzing activity at pH 3.2, about 70% of which does not cross-react with anti-rat liver cathepsin D antibody. A neutrophil non-cathepsin D acid proteinase was successfully isolated from cathepsin D and characterized in comparison with the properties of rat liver cathepsin D. The neutrophil enzyme differed from cathepsin D in chromatographic and electrophoretic behaviors as well as immunological cross-reactivity, and its molecular weight was estimated to be 98,000 by gel filtration on Toyopearl HW 55. These findings strongly suggest that the neutrophil enzyme could be classified as cathepsin E. The enzyme, now designated rat cathepsin E, had an optimal pH at 3.0-3.2, preferred hemoglobin to albumin as substrate, and was markedly resistant to urea denaturation. Rat cathepsins D and E cleaved the insulin B-chain at six and eight sites, respectively; five sites were common for both enzymes. Possible relations among cathepsin E and cathepsin D-like or E-like acid proteinases reported so far were discussed.

Amino Acid Sequence↗
PubMed1985

Preparation of cathepsins B and H by covalent chromatography and characterization of their catalytic sites by reaction with a thiol-specific two-protonic-state reactivity probe. Kinetic study of cathepsins B and H extending into alkaline media and a rapid spectroscopic titration of cathepsin H at pH 3-4.

A procedure for the isolation of cathepsin B (EC 3.4.22.1) and of cathepsin H from bovine spleen involving covalent chromatography by thiol-disulphide interchange and ion-exchange chromatography was devised. The stabilities of both cathepsins in alkaline media are markedly temperature-dependent, and reliable kinetic data can be obtained at pH values up to 8 by working at 25 degrees C with a continuous spectrophotometric assay. Both enzyme preparations contain only one type of thiol group as judged by reactivity characteristics towards 2,2'-dipyridyl disulphide at pH values up to 8; in each case this thiol group is essential for catalytic activity. Cathepsin H was characterized by kinetic analysis of the reactions of its thiol group with 2,2'-dipyridyl disulphide in the pH range approx. 2-8 and the analogous study on cathepsin B [Willenbrock & Brocklehurst (1984) Biochem. J. 222, 805-814] was extended to include reaction at pH values up to approx. 8. Cathepsin H, like the other cysteine proteinases, was shown to contain an interactive catalytic-site system in which the nucleophilic character of the sulphur atom is maintained in acidic media. The considerable differences in catalytic site characteristics detected by this two-protonic-state reactivity probe between cathepsin B, cathepsin H, papain (EC 3.4.22.2) and actinidin (EC 3.4.22.14) are discussed. Reaction with 2,2'-dipyridyl disulphide in acidic media, which is known to provide a rapid spectrophotometric active centre titration for many cysteine proteinases, is applicable to cathepsin H. This is useful because other active-centre titrations have proved unsuitable in view of the relatively low reactivity of the thiol group in cathepsin H.

2,2'-Dipyridyl↗
PubMed1991

S-S bridges of cathepsin B and H from bovine spleen: a basis for cathepsin B model building and possible functional implications for discrimination between exo- and endopeptidase activities among cathepsins B, H and L.

Bovine spleen cathepsin B contains 7 disulfide bridges. Using different chemical and enzymatic cleavage methods we isolated fragments representing the individual disulfides: Cys14-Cys43, Cys26-Cys71, Cys62-Cys128, Cys63-Cys67, Cys100-Cys132, Cys108-Cys119, and Cys148-Cys252. A similar line of approach was applied to determine the S-S bridges of bovine spleen cathepsin H: Cys23-Cys66, Cys57-Cys99, Cys157-Cys207, and Cys212-Cys5A, where Cys5A is located in the propart portion of the procathepsin H chain. On the basis of the knowledge of the S-S bridges of cathepsin B a novel sequence alignment of papain and cathepsin B has been proposed. This enabled us to construct a reasonable 3D-model of cathepsin B and propose the region (a 18 residue insertion between Glu89 and Gly90 of papain) responsible for the carboxypeptidase activity of cathepsin B functioning as a "closure". A similar approach was applied to explain the aminopeptidase activity of cathepsin H. A general model of steric regulation of accessibility of the preformed "endopeptidase-like" binding cleft by distant parts of the polypeptide chain of the proteinases discussed is proposed as a factor determining the mode of binding and thus cleavage of polypeptide substrates.

Amino Acid Sequence↗
PubMed1993

Serum cathepsin B levels, urinary excretion of cathepsin B and tissue cathepsin B content in the patients with gastric cancer.

Serum cathepsin B levels and urinary excretion of cathepsin B in the patients with gastric cancer were significantly higher than those in the control non-cancer patients. Moreover, cancer tissue cathepsin B content was significantly higher than that in the normal tissue. After radical curative operations for gastric cancers, both serum cathepsin B levels and urinary excretion of cathepsin B were restored to the control values. These results suggest a possible role of lysosomal enzyme, cathepsin B in the pathogenesis of tumor growth, and also suggest that these parameters might be possible indicators for tumor malignancy.

Aged↗
PubMed1981

Rat liver thiol proteinases: cathepsin B, cathepsin H and cathepsin L.

Data on following points of lysosomal thiol proteinases (cathepsins B, H and L) from rat liver are described in this paper: Partial amino acid sequence of cathepsin B, substrate specificity of cathepsin L, immunological studies of cathepsin B and H and effectiveness of E-64, specific thiol proteinase inhibitor in vivo.

Amino Acid Sequence↗
PubMed1976

Human skin proteases. Separation and characterization of two acid proteases resembling cathepsin B1 and cathepsin D and of an inhibitor of cathepsin B1.

Two acid proteases, one hydrolysing hemoglobin and the other hydrolysing benzoyl arginine naphthyamide (BANA), were separated and partially purified from human skin buffer extract. The acid protease hydrolysing hemoglobin was purified about 190 fold by Sephadex G-100 gel filtration and DEAE-cellulose chromatography. It hydrolysed hemoglobin at pH 3.5, casein at pH 5.8 and skin protein substrate at pH 6.0. It did not markedly hydrolyse synthetic protease substrates. The molecular size of this protease was 38000. The protease was insensitive to common protease modifiers and closely resembles cathepsin D purified from other organs. The BANA-hydrolysing acid protease was purified about 760 fold by Sephadex G-100 gel filtration and affinity chromatography on organomercurial Sepharose 4B gel. It preferentially hydrolysed BAEE, BANA and BAA with an optimum at pH 5.8. The hydrolysis of BAPA, LeuNA and protein substrates was very low. This acid protease was found to be highly dependent on reducing agents, as DTT, and chelating agents, as EDTA, and was inhibited by pCMB and TLCK. The molecular size of the enzyme was 28000. This protease closely resembles cathepsin B1 purified from other organs. Human skin was also shown to contain a low activity of benzoyl arginine amide (BAA) hydrolysing acid protease with a molecular size of about 50000 and resembling cathepsin B2. Human skin contained an inhibitor with a molecular size of about 13000 against human skin cathepsin B1. This inhibitor did not inhibit trypsin, chymotrypsin or skin proteases other than cathepsin B1.

Benzoylarginine-2-Naphthylamide↗
PubMed2000

Cathepsin B, a prognostic indicator in lymph node-negative breast carcinoma patients: comparison with cathepsin D, cathepsin L, and other clinical indicators.

New prognosticators are needed for breast cancer patients after the initial surgical treatment to make therapeutic decisions that ultimately will affect their DFS. These consist of specific proteolytic enzymes including lysosomal endopeptidases. In this study, the activity and protein concentrations of cathepsins (Cats) D, B, and L were measured in 282 invasive breast tumor cytosols. These potential biological prognostic indicators were compared with other histopathological parameters, such as tumor size, lymph node involvement, tumor-node-metastasis stage, histological grade, DNA analysis, and steroid receptors. CatD protein concentration correlated with lymph node involvement. CatB and CatL levels correlated significantly with Scarf-Bloom-Richardson histological grade and were also higher in estrogen-negative tumors, and CatB was higher in larger tumors. As prognostic markers, CatB concentration was significant for increased risk for recurrence in the entire patient population and specifically also in lymph node-negative patients as follows: high CatB concentration (above 371 micrograms/g) in tumor cytosols was significant (P < 0.00) for high risk of recurrence but was of only borderline prognostic significance (P < 0.06) for overall survival of all patients. In lymph node-negative patients, CatB (above 240 micrograms/g, P < 0.003) was highly significant for recurrence-free survival, followed by CatL (above 20 micrograms/g, P < 0.049) and CatD (above 45 nmol/g, P < 0.044) concentrations. For overall survival of node-negative patients, only CatB was a significant (P < 0.014) prognosticator. We conclude that CatB is useful as a prognostic indicator in lymph node-negative patients. This suggests that selective adjuvant therapy should be applied in this lower risk group of patients when high levels of CatB are determined.

Adult↗
PubMed1995

Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer.

The lysosomal cysteine proteases cathepsin B and cathepsin L have been implicated in tumor spread and metastasis. To evaluate the prognostic impact of these proteases for disease-free survival and overall survival in breast cancer, the antigen content of cathepsin B and cathepsin L was determined using ELISA in tumor cytosol fractions of 167 breast cancer patients and in cytosols of 29 benign breast tissue specimens. Median values of 856 ng versus 76 ng cathepsin B/mg protein and of 428 ng versus 56 ng cathepsin L/mg protein were found in tumor versus benign cytosol fractions. A positive correlation between cathepsin B and cathepsin L (r = 0.32, P = 0.0000, Spearman test) was found. Cathepsin L was inversely correlated to hormone receptor status (P = 0.0014, Mann-Whitney U test) and to the presence of tumor necrosis (P = 0.009, Mann-Whitney U test). There were no correlations of cathepsin B or cathepsin L to tumor size, axillary lymph node status, age, menopausal status, tumor grading, and vessel invasion. To perform univariate analyses of disease-free survival, optimal cutoff points were determined by isotonic regression and classification and regression trees analysis. Patients with a high content of cathepsin B (>1092 ng/mg protein) or cathepsin L (>376 ng/mg protein) in their primary tumors had a statistically significantly higher risk of recurrence than patients with a low content of cathepsin B or cathepsin L (5-year disease-free survival: cathepsin B, 70% versus 52%, P = 0.04; cathepsin L, 83% versus 52%, P = 0.0002). Median follow-up was 39 (range, 6-73) months. Multivariate analysis for disease-free survival showed that cathepsin L is a strong and independent prognostic factor with a prognostic impact comparable to that of axillary lymph node status and grading. We conclude that both cathepsin B and cathepsin L may serve as prognostic factors for tumor recurrence in human breast cancer. These data underline the significance of tumor-associated proteolysis for invasion and metastasis.

Adult↗
PubMed1976

Bovine spleen cathepsin B1 and collagenolytic cathepsin. A comparative study of the properties of the two enzymes in the degradation of native collagen.

Bovine spleen cathepsin B1 and collagenolytic cathepsin were separated by chromatography on Amberlite IRC-50 and collagenolytic cathepsin was partially purified by chromatography on DEAE-Sephadex (A-50). 2. Collagenolytic cathepsin degraded insoluble tendon collagen maximally at pH 3.5 and 28 degrees C; mainly alpha-chain components were released into solution. At 28 degrees C the telopeptides in soluble skin collagen were also cleaved to yield alpha-chain components. Collagenolytic cathepsin was thus similar to cathepsin B1 in its action against native collagen, but mixtures of these two enzymes exhibited a synergistic effect. 3. The addition of thiol-blocking compounds produced similar inhibition of collagenolytic cathepsin and cathepsin B1. The enzyme responded similarly to all other compounds tested except to 6-aminohexanoic acid, when collagenolytic cathepsin was slightly activated and cathepsin B1 was almost unaffected. 4. Leupeptin, which is a structural analogue of arginine-containing synthetic substrates, inhibited collagenolytic cathepsin as effectively as cathepsin B1. Collagenolytic cathepsin was shown to retain a low residual activity against alpha-N-benzoyl-DL-arginine p-nitroanilide during purification which was equivalent to 0.2% of the activity of cathepsin B1. 5. Cathepsin B1 and collagenolytic cathepsin could not be separated by affinity chromatography on organomercurial-Sepharose 4B. The two enzymes could be resolved on DEAE-Sephadex (A-50) and by isoelectric focusing in an Ampholine pH gradient. The pI of the major cathepsin B1 isoenzyme was 4.9 and the pI of collagenolytic cathepsin was 6.4. 6. From chromatography on Sephadex G-75 (superfine grade) the molecular weights were calculated to be 26000 for cathepsin B1 and 20000 for collagenolytic cathepsin. The difference in molecular weight was confirmed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis.

2,2'-Dipyridyl↗
PubMed2004

Cathepsin D, but not cathepsin E, degrades desmosomes during epidermal desquamation.

BACKGROUND: We previously reported that an ambient aspartic proteinase is crucial to desquamation of the stratum corneum at pH 5. Identification of this aspartic proteinase by using enzyme inhibitors suggested it to be cathepsin D, although we could not exclude cathepsin E. OBJECTIVES: To determine the identity of this aspartic proteinase and its distribution within the stratum corneum. METHODS: We measured enzyme activities of cathepsin D and cathepsin E in the salt and detergent extracts from callus stratum corneum, using a fluorogenic peptide as a substrate and comparing the effect of addition of Ascaris pepsin inhibitor (specific for cathepsin E) with that of pepstatin A (which inhibits both cathepsin D and cathepsin E). Both enzymes were then extracted and purified from plantar stratum corneum samples and identified by Western blotting. Immunofluorescence microscopy was used to investigate the localization of proteinases within human plantar stratum corneum sample sections. RESULTS: We found that 20% of total aspartic proteinase activity could be attributed to cathepsin E, the remainder to cathepsin D. Two subunits of cathepsin D were identified, a mature active form at 33 kDa and an intermediate active form at 48 kDa; cathepsin E was also identified at 48 kDa, although in a stained band 10-fold weaker in the immunoblot. Immunofluorescence microscopy showed the antibody to cathepsin D to be localized in the lipid envelopes of the stratum corneum, whereas that to cathepsin E stained the tissue diffusely. The labelling for cathepsin D was similar to that observed for desmosomes, and immunoelectron microscopy confirmed that cathepsin D was present on desmosomes. On the other hand, cathepsin E occurred intracellularly within the squames. CONCLUSIONS: We conclude that cathepsin D, and not cathepsin E, causes desquamation by degrading desmosomes.

Cathepsin D↗
PubMed1997

Specific catalytic activity of cathepsin S in comparison to cathepsins B and L along the rat nephron.

Assay conditions were elaborated to determine the catalytic activity of cathepsin S fluorometrically for direct comparison with the activities of cathepsins B + L(+S) and B along the nephron of the normal rat. These conditions include the use of 0.5 mM Z-Phe-Arg-AMC as substrate, which is saturating for the three enzymes. The stability of cathepsin S at pH 7.5 and the resistance of cathepsin B against inactivation by 0.5 microM Z-Phe-Phe-CHN2 permitted differentiation of these enzyme activities. The catalytic activity of cathepsin S in rat kidney homogenate (1.11 mumol/min x g protein) amounted to 2.1% of that of cathepsins B + L(+S) and to 3.2% of that of cathepsin B. It was ten-fold higher in the cortex (1.54 mumol/min x g protein) than in the medulla resembling the activity ratio of cathepsins B + L(+S) and B. In suspensions of isolated glomeruli and isolated proximal tubules the activities of cathepsin S were 0.76 and 3.21 mumol/min x g protein, respectively. The corresponding activities of cathepsins B + L(+S) amounted to 80.0 and 211.7 mumol/min x g protein consisting of 71% cathepsin B activity. In nephron segments microdissected from lyophilized renal sections, highest cathepsin S activity was found in the proximal convoluted tubules (4.21 mumol/min x g dry weight) followed by 0.83 mumol/min x g dry weight in proximal straight tubules of the superficial cortex. In the remaining segments cathepsin S activity was hardly detectable. Unlike cathepsin S activity, the activity of cathepsin B was distributed in parallel to that of cathepsins B + L(+S). The presence of relatively high cathepsin S activity in proximal convoluted tubules in co-localization with the activities of cathepsins B + L(+S) and B suggests a primary role of these enzymes in heterophagocytosis of proteins from the ultrafiltrate.

Animals↗
PubMed1999

Human cathepsins F and W: A new subgroup of cathepsins.

Human cathepsin F is a recently described papain-like cysteine protease of unknown function. To investigate the evolutionary relatedness to other human cathepsins, we determined the genomic organization and the chromosomal localization of cathepsin F and isolated its putative promoter region. The gene of human cathepsin F (CTSF) is composed of twelve exons and eleven introns and was found to be similar to that of cathepsin W but different from the cathepsins K, S, L, O, B, and C. The splice sites of nine out of the eleven introns were identical to those determined in the cathepsin W gene (CTSW), whereas introns one and ten were unique for CTSF. The 4. 7 kb gene was mapped to the long arm of chromosome 11 at position q13.1-3, a locus shared with CTSW. Phylogenetic analysis of human cathepsin protein sequences demonstrated that (i) cathepsins F and W are evolutionarily separated from other human cathepsins, and (ii) cysteine proteases closely related to human cathepsin W and F are also expressed in parasites and mammals. Based on these phylogenetic findings, on the presence of a particular protein motif ("ERFNAQ") in the propeptides of cathepsins F and W as well as the genomic organization and chromosomal localization of their genes, we concluded that F and W form a novel subgroup of cathepsin proteases. We suggest the naming "cathepsin F-like" proteases distinct from the previously described cathepsins "L- and B-like" subgroups.

Cathepsin F↗