UNIPROT:P01034 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peptidyl diazomethanes Cbz-Gly-CHN2, Boc-Val-Gly-CHN2, H-Leu-Val-Gly-CHN2, Cbz-Leu-Val-Gly-CHN2 and Cbz-Arg-Leu-Val-Gly-CHN2, with peptidyl portions modelled after the proposed cysteine proteinase interacting N-terminal segment of human cystatin C, were synthesized. Their efficiency as cysteine proteinase inhibitors was tested against papain, human cathepsin B and bovine cathepsin B. All, except Cbz-Gly-CHN2, were found to be irreversible inhibitors of the tested enzymes. Each addition of an amino acid residue to their peptidyl portions resulted in an increased inhibition rate of all three enzymes. These data suggest that the arginyl residue of the tetrapeptidyl diazomethane, and also the corresponding arginyl residue in native cystatin C, interact with a S4 substrate pocket subsite of both papain and cathepsin B. The most efficient inhibitor, Cbz-Arg-Leu-Val-Gly-CHN2, inhibited papain and cathepsin B with rate constants of the same order of magnitude as those for L-3-carboxy-trans-2,3-epoxypropionyl-leucylamido-(4-guanidin o)butane (E-64). The high water-solubility of Cbz-Arg-Leu-Val-Gly-CHN2 allowing it to be dissolved to molar concentrations without use of non-physiological additives, makes it suitable for in vitro and in vivo cysteine proteinase inhibition studies.
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PMID:Cystatin C based peptidyl diazomethanes as cysteine proteinase inhibitors: influence of the peptidyl chain length. 128 27

Expression of the cysteine proteinase cathepsin B and its physiological inhibitor cystatin C was analyzed in vitro in 1 human fibrosarcoma and 4 human colon carcinoma cell lines. Cystatin C antigen as well as cathepsin B activity were detected in the conditioned media of the 5 cell lines. The corresponding cell extracts expressed high levels of cathepsin B activity, whereas only trace amounts of cystatin C antigen could be found. Northern-blot analysis revealed the presence in the 5 cell lines of a 0.8-kb cystatin C mRNA transcript and 2 cathepsin B transcripts of 2.3 and 4.3 kb. Pepsin treatment of tumor-cell-released cathepsin B induced an average 7.3-fold increase in activity, indicating that the enzyme was mainly present as a latent form in conditioned medium. The pepsin-activated cathepsin B from one colon carcinoma cell line was further characterized using the cysteine proteinase inhibitors E-64, recombinant cystatin C, a cystatin-C-derived peptidyl inhibitor (Z-LVG-CHN2), and cathepsin-B-specific diazomethyl ketone inhibitors (Z-FT(OBzl)-CHN2, Z-FS(OBzl)-CHN2). This activity was totally neutralized by recombinant cystatin C, suggesting a potential for interaction between released extracellular cathepsin B and cystatin C. In vitro assays of degradation of extracellular matrix showed that cysteine proteinase inhibitors could decrease matrix degradation induced by pepsin-activated conditioned media. With colon cells, this inhibition was not observed, indicating a requirement for an extracellular activation of latent cathepsin B. Our data provide evidence that cystatin C and latent cathepsin B are both released extracellularly by colon carcinoma cells in vitro. They suggest that cystatin C and cathepsin B interactions may participate, in an as yet unelucidated way, in the modulation of the invasive phenotype of human colonic tumors.
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PMID:Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation. 139 47

Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids. Cystatin C and a tripeptide derivative (Z-LVG-CHN2) that mimics its proteinase-binding center, were tested for possible antiviral activity against herpes simplex virus type 1 (HSV) and poliovirus type 1. Both recombinant cystatin C and Z-LVG-CHN2 displayed strong inhibitory effects on HSV replication, whereas no significant effect on poliovirus replication was seen. The molar concentration of cystatin C that gave total inhibition of HSV replication was lower than that of either Z-LVG-CHN2 or of acyclovir, the drug currently most used against HSV infections. These results suggest that cysteine proteinase inhibitors might play a physiological role as inhibitors of viral replication and that such proteinase inhibitors, or peptide derivatives that mimic their proteinase-binding centers, might be used as antiviral agents.
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PMID:Cystatin C, a human proteinase inhibitor, blocks replication of herpes simplex virus. 215 54

Cysteine proteinases are important not only in the intracellular catabolism of peptides and proteins and in the processing of prohormones and proenzymes, but also in the penetration of normal human tissue by malignant cells and possibly microorganisms, including viruses. Cystatin C is a human cysteine proteinase inhibitor present in extracellular fluids. We have synthesized peptide derivatives mimicking the proposed proteinase-binding centre of cystatin C and find that they irreversibly inhibit cysteine proteinases. Several bacteria produce proteinases, so we tested a tripeptide derivative (Z-LVG-CHN2) for in vitro anti-bacterial activity against a large number of bacterial strains belonging to thirteen different species. It was found to inhibit specifically the growth of all strains of group A streptococci. The susceptibility of these human pathogens to the peptide was compared with that to well-established anti-streptococcal antibiotics such as tetracycline and bacitracin. Moreover, the peptide was active in vivo against group A streptococci: mice injected with lethal doses of these bacteria were cured by a single injection of Z-LVG-CHN2. The cysteine proteinase produced by group A streptococci was isolated and found to be inhibited by Z-LVG-CHN2; moreover, excess proteinase relieved the growth inhibition caused by the peptide derivative, suggesting that the antibacterial activity of Z-LVG-CHN2 is due to inhibition of this cysteine proteinase. This strategy of blocking proteinases with peptide derivatives that mimic naturally occurring inhibitors could be useful in the construction of new agents against other microorganisms, including viruses.
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PMID:Bacterial growth blocked by a synthetic peptide based on the structure of a human proteinase inhibitor. 264 59

Macrophages are thought to play an important role in the turnover of extracellular matrix, but the capacity of human macrophages to degrade elastin, and the elastolytic mechanisms of these cells, have been controversial. Particular difficulty has been encountered in efforts to establish whether human macrophages secrete a metalloelastase that is analogous to the enzyme secreted by rodent macrophages. We studied elastin degradation by human alveolar macrophages cultured directly in contact with radiolabeled elastin using media containing 10% fetal bovine serum, and for comparison performed parallel studies of P388D1 murine macrophagelike cells that are known to secrete metalloelastase. With both cell types, we observed elastin degradation and the following: (1) direct contact between the cells and elastin substrate was required for elastin degradation; (2) elastin degradation was inhibited by the tissue inhibitor of metalloproteinases, but minimally or not at all by inhibitors of cysteine proteinases (E-64, CBZ-phe-phe-CHN2, CBZ-phe-ala-CHN2, and cystatin C), or by the serine proteinase inhibitor eglin-c; (3) elastin degradation increased sharply after the cells were in contact with elastin for 24 h, and required new protein synthesis as indicated by sensitivity to cycloheximide; (4) inclusion of dexamethasone (10(-6) to 10(-8) M) in the cultures led to decreased elastin degradation. Also, with both cell types, elastin degradation occurred despite the finding that cell-conditioned media did not contain elastase activity and could inhibit P388D1-derived metalloproteinase elastase. These results indicate a prominent role for metalloproteinase activity in elastin degradation by both human and murine macrophages and support the concept that events at the cell-substrate interface are critically important to macrophage-mediated elastin degradation.
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PMID:Elastin degradation by human alveolar macrophages. A prominent role of metalloproteinase activity. 271 52

Procathepsin L, the precursor to a powerful lysosomal cysteine proteinase, has been purified to apparent homogeneity from guinea pig spermatozoa, a novel and previously unrecognized source of this catalytically active zymogen. In the range of pH 5.0, procathepsin L (39,000 M(r)) readily self-processed yielding a mature, single-chain proteinase (29,000 M(r)) and an intact propeptide (10,000 M(r)) by what appeared kinetically to be an intramolecular reaction mechanism. These characteristics resembled those reported for the "major excreted protein" (MEP) of malignantly transformed mouse fibroblasts-a protein that has been characterized as the precursor to the mouse analog of human cathepsin L (B. R. Troen, S. Gal, and M. M. Gottesman (1987) Biochem. J. 246, 731-735). Other characteristics shared by the guinea pig and mouse zymogens included proteolytic activity at pH 5.0, homologous N-terminal amino acid sequences, and immunological relatedness. It was thus concluded that acrosomal procathepsin L is the guinea pig analog of MEP. Acrosomal procathepsin L had a specific activity on benzyloxy-carbonyl-Phe-Arg-7-(4-methyl)coumarylamide (Z-Phe-Arg-NMec) of 30 mumol min-1 mg-1 enzyme at pH 3.2 and 37 degrees C. Relative to the assay substrate, rates on other fluorogenic substrates were 90% for Z-Phe-Cit-NMec, 63% for Z-Leu-Leu-Arg-NMec, 43% for D-Phe-Ser(Bzl)-Phe-Phe-Ala-Ala-p-aminobenzoate (a "specific" cathepsin D assay substrate), and 32% for Z-Val-Val-Arg-NMec. No action was detected on Z-Arg-Arg-NMec or Arg-NMec. Mature cathepsin L showed the same relative order of substrate specificity as its proenzyme form, but the absolute rates were about 5-fold greater. Additionally, the mature (single-chain) form of cathepsin L displayed Km and kcat values on Z-Phe-Arg-NMec that yielded an exceptionally high catalytic coefficient (11,600 s-1 mM-1) compared to values reported for two-chain forms of cathepsin L. Self-processing by acrosomal procathepsin L at pH 5.5 was totally inhibited by leupeptin, cystatin C, Ep-475, and Z-Phe-Phe-CHN2 at 1 microM levels. Gossypol (0.1 mM) gave 94% inhibition. Interestingly, dextran sulfate (100 micrograms ml-1) gave a 3.6-fold increase in the rate of self-processing seen at pH 5.5--a phenomenon of potential physiological relevance in view of the high-negative-charge density present within the hyaluronic acid-rich outer layer (cumulus oophorus) of the ovum.
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PMID:Purification and characterization of procathepsin L, a self-processing zymogen of guinea pig spermatozoa that acts on a cathepsin D assay substrate. 748 6

'Prohormone thiol protease' (PTP) represents the major enkephalin precursor processing activity in chromaffin granules. In this study, cleavage specificity of PTP for paired basic and monobasic residues was examined with a series of model peptide-MCA (-methylcoumarinamide) substrates. Monobasic peptides were cleaved at the COOH- and NH2-terminal sides of the single basic residue. Dibasic peptides, however, were preferentially cleaved at the NH2-terminal side of the pair, or between the two basic residues, with low cleavage at the COOH-terminal side of the pair. Inhibition by the peptide inhibitor (D-Tyr)-Glu-Phe-Lys-Arg-CH2Cl provided further evidence for PTP's specificity for the dibasic Lys-Arg site. Inhibition by Z-Leu-Val-Gly-CHN2 and Z-Arg-Leu-Val-Gly-CHN2 suggests involvement of Val-Gly in substrate binding to PTP; these two cystatin C-related inhibitors also indicate PTP as a cysteine protease. These results demonstrate PTP's unique cleavage specificity that differs from other processing endopeptidases, including the subtilisin-related proprotein convertases, PC1/PC3, and PC2, as well as the pituitary proopiomelanocortin-converting enzyme, PCE. This study provides further evidence for PTP as a novel prohormone processing enzyme that belongs to the class of cysteine proteases.
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PMID:Unique cleavage specificity of 'prohormone thiol protease' related to proenkephalin processing. 813 39

Urinary excretion of five low molecular weight proteins (LMWP) [beta 2-microglobulin (beta 2m), cystatin C (cyst C), Clara cell protein (CC16), retinol-binding protein (RBP) and alpha 1-microglobulin (alpha 1m)], albumin and N-acetyl-beta-D-glucosaminidase (NAG) were quantified in 16 patients who followed a weight reduction program which included Chinese herbs, which have been incriminated in the genesis of Chinese herbs nephropathy (CHN). An additional group of four patients transplanted for CHN were investigated. Urinary data were obtained for comparison purpose in five groups of proteinuric patients: two groups with normal serum creatinine (SCr) and glomerular albuminura [12 patients with diabetes mellitus and microalbuminuria (DN), 10 patients with primary nephrotic syndrome (NS)]; two groups with normal SCr and toxic nephropathy [6 patients with analgesic (AN), 9 patients with cadmium nephropathy (CdN)]; and one group of seven patients with glomerular diseases and increased SCr (GN). Patients were classified according to serum level S beta 2m to take into account the possibility of overflow proteinuria at S beta 2m > or = 5 mg/liter. Three patients (CHN0) with a S beta 2m < 5 mg/liter, had a normal urinary protein pattern including NAG and a normal S beta 2m. Eight patients (CHN1) with a S beta 2m < 5 mg/liter had various abnormalities of their urinary protein pattern. In four of them (CHN1a) only beta 2m, RBP and CC16 were increased while total proteinuria and SCr were normal. In the other four (CHN1b and c) albumin, cyst C, alpha 1m and NAG were also elevated, while total proteinuria and SCr were moderately raised. Five patients (CHN2) with a S beta 2m > or = 5 mg/liter had a markedly increased excretion of all LMWP, albumin and NAG (CHN1 vs. CHN2, P < 0.05) as well as a further increase in total proteinuria and SCr. The urinary LMWP/albumin concentration ratio was strikingly higher in CHN patients than in patients with glomerular albuminuria (CHN1 vs. DN and NS, P < 0.01) or moderate renal failure with elevated S beta 2m level (CHN2 vs. GN, P < 0.01), confirming the existence of a tubular proteinuria independent of glomerular albuminuria or overflow proteinuria. A similar proteinuria pattern was present in the two toxic nephropathies (CdN and AN). This pattern was no longer recognizable after transplantation. In conclusion, CHN exhibits various profiles of tubular proteinuria which are the hallmarks of the disease. This pattern is still detectable in patients with renal failure and/or glomerular albuminuria. It is identical to that observed in cadmium and analgesic nephropathies. It does not recur after transplantation. Its most sensitive and reliable marker is a raised urinary level of CC16 or RBP.
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PMID:Low molecular weight proteinuria in Chinese herbs nephropathy. 854 16

Biotin-labelled peptidyl diazomethane inhibitors of cysteine proteinases, based on the N-terminal substrate-like segment of human cystatin C, a natural inhibitor of cysteine proteinases, were synthesized. These synthetic derivatives were tested as irreversible inhibitors of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, to compare the kinetics of the inhibition of the parasite proteinase with that of the mammalian cathepsins B and L. The accessibility of the active sites of these proteinases to these probes was also investigated. The inhibition of cruzipain by Biot-LVG-CHN2 (where Biot represents biotinyl and L,V and G are single-letter amino acid residue abbreviations) and Biot-Ahx-LVG-CHN2 (where Ahx represents 6-aminohexanoic acid) was similar to that of unlabelled inhibitor. Biotin labelling of the inhibitor slowed the inhibition of both cathepsin B and cathepsin L. Adding a spacer arm (Ahx) between the biotin and the peptide moiety of the derivative increased the inhibition of cathepsin B but not that of cathepsin L. The discrimination provided by this spacer is probably due to differences in the topologies of the binding sites of proteinases, a feature that can be exploited to improve targeting of individual cysteine proteinases. Analysis of the blotted proteinases revealed marked differences in the accessibility of extravidin-peroxidase conjugate to the proteinase-bound biotinylated inhibitor. Cruzipain molecules exposed to Biot-LVG-CHN2 or Biot-Ahx-LVG-CHN2 were readily identified, but the reaction was much stronger when the enzyme was treated with the spacer-containing inhibitor. In contrast with the parasite enzyme, rat cathepsin B and cathepsin L treated with either Biot-LVG-CHN2 or Biot-Ahx-LVG-CHN2 produced no detectable bands. Papain, the archetype of this family of proteinases, was poorly labelled with Biot-LVG-CHN2, but strong staining was obtained with Biot-Ahx-LVG-CHN2. These findings suggest that optimized biotinylated diazomethanes might considerably improve their selectivity for the T. cruzi target enzyme.
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PMID:Biotin-labelled peptidyl diazomethane inhibitors derived from the substrate-like sequence of cystatin: targeting of the active site of cruzipain, the major cysteine proteinase of Trypanosoma cruzi. 880 25

The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.
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PMID:Osteoclastogenesis is decreased by cysteine proteinase inhibitors. 1500 89

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