Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous cathepsin B-like protein sequences (CBLs) have been reported from nematodes. However, the relationships among these proteins remain unclear. Here, expression of several CBL transcripts in the gut of the parasitic nematode Haemonchus contortus was demonstrated. To assess potential functional diversity, multiple nematode CBL sequences were compared with known functional domains of cathepsin B. These domains included the occluding loop, S2' and S2 subsites, and the pro region. Four groups of CBLs were defined based on variable characteristics in the occluding loop region, which incorporates a portion of the S2' subsite. Further diversity was observed in amino acids expected to contribute to the S2 subsite. In addition, short signature sequences near the cysteinyl active site region characterized known CBLs of parasites from the orders Strongylida and Rhabditida. The criteria established were used to identify two predicted CBLs from parasitic (Ascaris suum) and free-living (Caenorhabditis elegans) nematodes as potential orthologues, and provided a basis to evaluate orthologue status of other CBLs. Variability in the domains analyzed suggests substantial functional diversity in enzymatic properties of nematode CBLs. Results suggest that the selective amplification and evolution of distinct CBL lineages has contributed to differences in CBLs among species and groups of nematodes. Nutrient digestion is one potential factor promoting CBL diversification in these organisms.
Mol Biochem Parasitol 1999 Aug 20
PMID:Defined characteristics of cathepsin B-like proteins from nematodes: inferred functional diversity and phylogenetic relationships. 1049 85

Human cathepsin X is one of many proteins discovered in recent years through the mining of sequence databases. Its sequence shows clear homology to cysteine proteases from the papain family, containing the characteristic residue patterns, including the active site. However, the proregion of cathepsin X is only 38 residues long, the shortest among papain-like enzymes, and the cathepsin X sequence has an atypical insertion in the regions proximal to the active site. This protein was recently expressed and partially characterized biochemically. Unlike most other cysteine proteases from the papain family, procathepsin X is incapable of autoprocessing in vitro but can be processed under reducing conditions by exogenous cathepsin L. Atypically, the mature enzyme is primarily a carboxypeptidase and has extremely poor endopeptidase activity. We have determined the three-dimensional structure of the procathepsin X at 1.7 A resolution. The overall structure of the mature enzyme is characteristic for enzymes of the papain superfamily, but contains several novel features. Most interestingly, the short proregion binds to the enzyme with the aid of a covalent bond between the cysteine residue in the proregion (Cys10p) and the active site cysteine residue (Cys31). This is the first example of a zymogen in which the inhibition of enzyme's proteolytic activity by the proregion is achieved through a reversible covalent modification of the active site nucleophile. Such mode of binding requires less contact area between the proregion and the enzyme than observed in other procathepsins, and no auxiliary binding site on the enzyme surface is used. A three-residue insertion in a highly conserved region, just prior to the active site cysteine residue, confers a significantly different shape on the S' subsites, compared to other proteases from papain family. The 3D structure provides an explanation for the rather unusual carboxypeptidase activity of this enzyme and confirms the predictions based on homology modeling. Another long insertion in the cathepsin X amino acid sequence forms a beta-hairpin pointing away from the active site. This insertion, thought to be an equivalent of cathepsin B occluding loop, is located on the side of the protein, distant from the substrate binding site.
J Mol Biol 2000 Jan 28
PMID:Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. 1065 2

Rheumatoid arthritis (RA) and osteoarthritis (OA) are the major types of arthritis. Although both diseases are characterized by joint destruction, their etiologies are different. To get insights into pathophysiological pathways, we used the suppression subtractive hybridization (SSH) method to identify differentially expressed genes in RA. DNA sequencing identified 12 gene products including cytoskeletal gamma-actin and extracellular matrix components such as fibronectin, collagen III alpha(1), and superficial zone protein. Interferon gamma-inducible genes such as a novel thiol reductase, two genes of unknown function (HSIFNIN4, RING3), and annexin II were also found. Two genes encoded proteins involved in proliferation such as elongation factor 1 alpha and the granulin precursor. Furthermore, the protease cathepsin B and synovial phospholipase A2 group IIA were detected by SSH. To confirm the differential expression of the genes, we performed RT-PCR analyses of RA and OA synovial tissues. Compared to OA patients, 9 of the 12 genes were overexpressed in RA, suggesting that SSH is a powerful tool for the detection of differential gene expression in synovial tissues. Further characterization of the gene products may help to identify pathophysiological mechanisms in arthritic diseases.
Mol Cell Biol Res Commun 2000 Mar
PMID:Differential gene expression in synovium of rheumatoid arthritis and osteoarthritis. 1086 Aug 65

Satellite myoblasts serve as stem cells in postnatal skeletal muscle, but the genes responsible for choosing between growth versus differentiation are largely undefined. We have used a novel genetic approach to identify genes encoding proteins whose dominant negative inhibition is capable of interrupting the in vitro differentiation of C2C12 murine satellite myoblasts. The screen is based on fusion of a library of cDNA fragments with the lysosomal protease cathepsin B (CB), such that the fusion protein intracellularly diverts interacting factors to the lysosome. Among other gene fragments selected in this screen, including those of known and novel sequence, is the retinoblastoma protein (RB) pocket domain. This unique dominant negative form of RB allows us to genetically determine if MyoD and RB associate in vivo. The dominant negative CB-RB fusion produces a cellular phenotype indistinguishable from recessive loss of function RB mutations. The fact that the dominant negative RB inhibits myogenic differentiation in the presence of nonlimiting concentrations of either RB or MyoD suggests that these two proteins do not directly interact. We further show that the dominant negative RB inhibits E2F1 but cannot inhibit a forced E2F1-RB dimer. Therefore, E2F1 is a potential mediator of the dominant negative inhibition of MyoD by CB-RB during satellite cell differentiation. We propose this approach to be generally suited to the investigation of gene function, even when little is known about the pathway being studied.
Mol Cell Biol 2000 Jul
PMID:Selection of a dominant negative retinoblastoma protein (RB) inhibiting satellite myoblast differentiation implies an indirect interaction between MyoD and RB. 1086 69

Cathepsin B is an ancient family of eukaryotic cysteine proteases. We describe PsCat1, a plant cathepsin B-like transcript, identified as an expressed sequence in Rhizobium-induced, nitrogen-fixing root nodules of pea. In situ hybridization studies in root nodules showed strong, extremely localized expression of PsCat1 in individual cells associated with the central infected tissue. Restriction fragment polymorphism mapping of the PsCat1 locus in pea shows no correlation with existing mutant lines defective in symbiosis.
Mol Plant Microbe Interact 2000 Jul
PMID:Localized expression of cathepsin B-like sequences from root nodules of pea (Pisum sativum). 1087 38

The therapeutic potential of synthetic inhibitors to the major cysteine-proteinase from Trypanosoma cruzi (cruzain or cruzipain) was recently demonstrated in animal models of Chagas' disease. A possible limitation of this strategy would be the emergence of parasite populations developing resistance to cysteine-proteinase inhibitors. Here, we describe the properties of a phenotypically stable T. cruzi cell line (R-Dm28) that displays increased resistance to Z-(SBz)Cys-Phe-CHN2, an irreversible cysteine-proteinase inhibitor which preferentially inactivates cathepsin L-like enzymes. Isolated from axenic cultures of the parental cells (IC50 1.5 microM), R-Dm28 epimastigotes exhibited 13-fold (IC50) 20 microM) higher resistance to this inhibitor and did not display cross-resistance to unrelated trypanocidal drugs, such as benznidazol and nifurtimox. Western blotting (with mAb), affinity labeling (with biotin-LVG-CHN2) and FACS analysis of R-Dm28 log-phase epimastigotes revealed that the cruzipain target was expressed at lower levels, as compared with Dm28c. Interestingly, this deficit was paralleled by increased expression of an unrelated Mr 30 000 cysteine-proteinase whose activity was somewhat refractory to inhibition by Z-(SBz)Cys-Phe-CHN,. N-terminal sequencing of the affinity-purified biotin-LVG-proteinase complex allowed its identification as a cathepsin B-like enzyme. Increased antigenic deposits of this proteinase were found in the grossly enlarged and electron dense reservosomes from R-Dm28 epimastigotes. Our data suggest that R-Dm28 resistance to toxic effects induced by the synthetic inhibitor may result from decreased availability of the most sensitive cysteine-proteinase target, cruzipain. The deficit in metabolic functions otherwise mediated by this cathepsin L-like proteinase is likely compensated by increased expression/accumulation of a cathepsin B-like target.
Mol Biochem Parasitol 2000 Jun
PMID:Altered expression of cruzipain and a cathepsin B-like target in a Trypanosoma cruzi cell line displaying resistance to synthetic inhibitors of cysteine-proteinases. 1092 56

To study whether moderate under-nutrition causes muscle wasting, reindeer (Rangifer tarandus tarandus L.) calves were fed either pelleted reindeer feed ad libitum (n=8) or restricted amounts of lichens (n=8). The restricted amount was 60% of ad libitum intake of lichens, and the feeding period was 6 weeks preceded by a 2-week adjustment period. Biopsy samples from the middle gluteal muscle (M. gluteus medius) for the analysis of fibre composition and area, as well as for the activity of cathepsin B were taken before the restriction period in November and January, and after the restriction period in April. In all calves the muscle fibre composition remained unchanged during the winter. In the lichen group, the fibre size also remained unchanged, whereas in control calves the cross sectional area of type I and type IIA fibres increased significantly from November to April. Cathepsin B activity decreased in all calves from November to January and remained at that low level for the rest of the study period, which suggests an attenuated rate of protein degradation. These results can be taken as an indication that moderate under-nutrition causes no muscle wasting in reindeer calves, and the decreased availability of nitrogen is partially compensated for by adaptive decrease in protein degradation. Interestingly the adaptive changes in protein metabolism are equally well seen in the well-fed controls as in the undernourished lichen-fed reindeer.
Comp Biochem Physiol A Mol Integr Physiol 2001 Jun
PMID:Muscle fibre growth in undernourished reindeer calves (Rangifer tarandus tarandus L.) during winter. 1142 19

Human cathepsin B (CTSB) is a proteolytic enzyme implicated in tumor invasion and metastasis. We describe a PCR-based polymorphic marker for this gene comprising two amplimers differing in length by 19 consecutive nucleotides in intron 7, near the exon 8 splice acceptor site, identifying two gene alleles (A and B). Allele frequencies were 0.614 for A and 0.386 for the B allele, with an observed heterozygosity of 0.457 in a cohort of 70 non-related Australian blood donors. One additional nucleotide difference was also revealed through sequencing. The human CTSB gene is located on chromosome 8 and the alleles described here can potentially be used as markers in linkage and association studies of cancers and other diseases.
Mol Cell Probes 2001 Aug
PMID:A polymorphic marker for the human cathepsin B gene. 1151 59

Proteins expressed by nematode intestinal cells are potential targets for parasite control by immune or chemical based strategies. To expand our knowledge on nematode intestinal proteins, expressed sequence tags were generated for 131 cDNA clones from the intestine of adult female Haemonchus contortus. An estimated 55 distinct protein genes or gene families were identified. Predicted proteins represented diverse functions. Several predicted polypeptides were related to H. contortus proteins implicated in inducing protective immunity against challenge infections of this parasite. The dominant intestinal transcripts were represented by cathepsin B-like cysteine protease genes (cbl) (17% of protein coding expressed sequence tags (ESTs) analyzed). An estimated 11 previously undescribed cbl genes were identified, doubling the recognized members of this gene family. Multiple C-type lectin sequences were identified. Other notable sequences included a predicted Y-box binding protein, serine/threonine kinases and a cyclin E-like sequence. Predicted protein homologues were found in Caenorhabditis elegans for all but one H. contortus sequence (99%), while fewer homologues from other parasitic nematodes were found. Many of the proteases, lipase and C-type lectin homologues in C. elegans had apparent signal peptides, suggesting that they are secreted. Several gene products had no obvious similarity outside the phylum Nematoda. The ESTs identified intestinal genes with potential application to immune control, understanding of basic intestinal regulatory processes and refinement of nematode genomic resources.
Mol Biochem Parasitol 2001 Sep 03
PMID:Cathepsin B-like cysteine proteases and Caenorhabditis elegans homologues dominate gene products expressed in adult Haemonchus contortus intestine. 1152 49

By using RT-PCR and 5'- and 3'-RACE methods, we isolated cathepsin B cDNA from hemocytes of Bombyx mori. The predicted open reading frame encoded 337 amino acids with 54% identity with the human cathepsin B, and 55% identity with the 29-kDa proteinase of the blowfly. Three active sites characteristic for cathepsin B were conserved in the deduced amino acid sequences of BmCtB cDNA at positions Cys-111, His-280 and Asn-300. Northern analysis identified a 1.3-kb mRNA. Expression of BmCtB was observed in the hemocytes from the day of wandering and was strongest at day 1 pupa. With in situ hybridization, strong signals were observed in the granular cells and plasmatocytes of day 0 pupa, but not in those of day 5 of the fifth larval instar. The results indicate another function of cathepsin B and insect hemocyte during metamorphosis.
Comp Biochem Physiol B Biochem Mol Biol 2001 Oct
PMID:Isolation and expression of cathepsin B cDNA in hemocytes during metamorphosis of Bombyx mori. 1156 2


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