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

Leucocyte elastase in catalytic amounts was observed to rapidly cleave the Val-10-Gly-11 bond of the human cysteine-proteinase inhibitor cystatin C at neutral pH. The resulting modified inhibitor had size and amino acid composition consistent with a cystatin C molecule devoid of the N-terminal Ser-1-Val-10 decapeptide. Leucocyte-elastase-modified cystatin C had more than 240-fold lower affinity than native cystatin C for papain. Removal of the N-terminal decapeptide of human cystatin C also decreased inhibition of human cathepsins B and L by three orders of magnitude, but decreased inhibition of cathepsin H by only 5-fold. A tripeptidyldiazomethane analogue of of the N-terminal portion of cystatin C was a good inhibitor of cathepsins B and L but a poor inhibitor of cathepsin H. It therefore appears that amino acid side chains of the N-terminal segment of cystatin C bind in the substrate-binding pockets of cathepsins B and L but not in those of cathepsin H. It is argued that the N-terminal cystatin C interaction with cathepsin B is physiologically important and hence that leucocyte elastase could have a function as a regulator of extracellular cysteine-proteinase inhibitory activity at sites of inflammation.
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PMID:Human cystatin C. role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase. 199 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

Staphylococcus aureus is known to produce three very active extracellular proteinases. One of these enzymes, a cysteine proteinase, after purification to homogeneity was found to degrade insoluble bovine lung elastin at a rate comparable to human neutrophil elastase. This enzyme had no detectable activity against a range of synthetic substrates normally utilized by elastase, chymotrypsin, or trypsin-like proteinases. However, it did hydrolyze the synthetic substrate carbobenzoxy-phenylalanyl-leucyl-glutamyl-p-nitroanilide (Km = 0.5 mM, kcat = 0.16 s-1). The proteolytic activity of the cysteine proteinase was rapidly and efficiently inhibited by alpha 2-macroglobulin and also by the cysteine-specific inhibitor rat T-kininogen (Ki = 5.2 X 10(-7) M). Human kininogens, however, did not inhibit. Human plasma apparently contains other inhibitors of this enzyme, since plasma depleted of alpha 2-macroglobulin retained significant inhibitory capacity. The elastolytic activity of this S. aureus proteinase and its lack of control by human kininogens or cystatin C may explain some of the connective tissue destruction seen in bacterial infections due to this and related organisms such as may occur in septicemia, septic arthritis, and otitis.
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PMID:Degradation of elastin by a cysteine proteinase from Staphylococcus aureus. 342 37

Procathepsin B and cystatin C are found in human lung secretions. We investigated the capacity of human bronchial epithelial cells to synthesize and secrete these proteins. Immunoprecipitation of [35S]methionine-labeled proteins from cultured bronchial epithelial cell lysates, followed by denaturing gel electrophoresis and autoradiography, showed the presence of newly synthesized procathepsin B of M(r) 42,000; no mature form was detected. Cathepsin B in conditioned medium from epithelial cells was tagged with benzyloxycarbonyl-125I-tyrosyl-alanine-diazomethane before and after treatment of the medium with neutrophil elastase. Control medium again showed a predominant form of cathepsin B with a M(r) of 42,000, but upon treatment with neutrophil elastase this protein was converted to a M(r) of 38,000, similar to the active form previously found in lung secretions, and cathepsin B activity was generated. The medium also contained the cathepsin B inhibitor, cystatin C, but cystatins A, B, S, SN, SA, and kininogen were not detected. After removal of cystatin C from the medium, elastase was still required to activate procathepsin B. These results suggest that bronchial epithelial cells are a source of procathepsin B and cystatin C in lung secretions. Cleavage both of cystatin C and procathepsin B by neutrophil elastase is essential for the generation of cathepsin B activity in the medium.
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PMID:Synthesis and secretion of procathepsin B and cystatin C by human bronchial epithelial cells in vitro: modulation of cathepsin B activity by neutrophil elastase. 787 98

Vanadium has an antibacterial activity against Pseudomonas aeruginosa, especially under conditions of iron limitation. Some degree of resistance to V is inducible by prior exposure to the metal. One mutant (VS1) with a higher sensitivity to V was obtained by transposon mutagenesis of P. aeruginosa PA 59.20, a clinical isolate. This mutant had an insertion in a non-coding region, upstream of a cluster of four genes. Three of them show similarities to genes corresponding to known P. aeruginosa antibiotic efflux systems, including an efflux protein, a membrane fusion protein and an outer-membrane porin. This cluster was named mexGHI-opmD. By allelic exchange, three mutants, ncr (for non-coding region), mexI and opmD were constructed in P. aeruginosa PAO1. Next to V sensitivity, the ncr, mexI and opmD mutants also showed reduced production of elastase, rhamnolipids, pyocyanine, pyoverdine and had reduced swarming motility, phenotypes that are known to be regulated by quorum sensing. All wild-type phenotypes, including growth in the presence of V, were restored by complementation with the complete cluster. The production of N-acyl-homoserine lactones (AHLs) was detected using the Chromobacter violaceum bioassay. Total extracts from the three mutants failed to induce the production of violacein by C. violaceum, although AHLs were detected by TLC and C. violaceum overlay. Violacein production was restored by complementation with mexGHI-opmD. The opmD mutant grew very slowly in LB or CAA medium, indicating that OpmD has an important physiological function for the cell. In conclusion, it is believed that the MexGHI-OpmD pump is probably involved in AHL homeostasis in P. aeruginosa.
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PMID:Characterization of a new efflux pump, MexGHI-OpmD, from Pseudomonas aeruginosa that confers resistance to vanadium. 1217 31

Atherosclerosis and diabetes are closely associated and both involve extensive degradation of the aortic elastin. Increased elastase activity has been detected in diabetic animal aortae. We have demonstrated enhanced elastolytic cathepsin S in human atherosclerotic lesions but insufficient amounts of its endogenous inhibitor cystatin C, suggesting alterations of serum cathepsin S and/or cystatin C in patients with atherosclerosis or diabetes. In this study, we measured levels of both cathepsin S and cystatin C in sera from 240 patients by ELISA. Among these patients, 107 had a diagnosis of atherosclerotic stenosis, 103 were diabetic, and 30 had neither condition. Multiple linear regression analysis demonstrated that significantly higher serum levels of cathepsin S in patients with either atherosclerotic stenosis (p<0.04) or diabetes (p=0.0005) persisted after adjustment for cystatin C level, renal function, smoking, and serum glucose levels (p=0.008, p=0.0005). Furthermore, patients with acute (p=0.009) or previous myocardial infarction (p<0.02) or unstable angina pectoris (p<0.05) had elevated levels of cathepsin S after adjustment for smoking, creatinine, cystatin C, and serum glucose. In contrast, serum cystatin C levels were higher in diabetic patients (p=0.00001), but not in atherosclerotic subjects (p=0.14), than in the non-involved population after adjustment for age, smoking, and renal function. Although the pathophysiology of cathepsin S or cystatin C in atherosclerosis and diabetes requires further investigation, increased serum cathepsin S may serve as a biomarker for both diseases.
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PMID:Increased serum cathepsin S in patients with atherosclerosis and diabetes. 1614 Mar 6

Recent evidence indicates that failure of elastic fiber assembly and synthesis is involved in the pathophysiology of pelvic organ prolapse in mice. It has been long been hypothesized that parturition-induced activation of proteases in the vaginal wall and its supportive tissues may contribute to pelvic organ prolapse in women. In this investigation, we determined the expression of matrix metalloproteases with elastase activity (matrix metalloproteinase [MMP] 2, MMP9, and MMP12) and their inhibitors in the vaginal wall of nonpregnant, pregnant, and postpartum mice. Data obtained using mRNA levels and enzyme activity measurements indicate that MMP2, MMP9, and 21- to 24-kDa caseinolytic serine proteases are regulated in vaginal tissues from pregnant and postpartum mice. Although suppressed during pregnancy and the early postpartum time period, MMP2 and MMP9 enzyme activities are increased after 48 h, a time when mRNA levels of protease inhibitors (tissue inhibitor of MMP2 [Timp2], cystatin C [Cst3], and alpha-1 antitrypsin [Serpina1]) are decreased. We conclude that recovery of the vaginal wall from pregnancy and parturition requires increased elastic fiber assembly and synthesis to counteract the marked increase in elastolytic activity of the postpartum vagina.
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PMID:Regulation of elastolytic proteases in the mouse vagina during pregnancy, parturition, and puerperium. 1800 50

Abdominal aortic aneurysm (AAA) is an important health problem. Elective surgical treatment is recommended on the basis of an individual's risk of rupture, which is predicted by AAA diameter. However, the natural history of AAA differs between patients and a reliable and individual predictor of AAA progression (growth and expansion rates) has not been established. Several circulating biomarkers are candidates for an AAA diagnostic tool. However, they have yet to meet the triad of biomarker criteria: biological plausibility, correlation with AAA progression, and prediction of treatment effect on disease outcome. Circulating levels of markers of extracellular matrix degeneration, such as elastin peptides, aminoterminal propeptide of type III procollagen, elastase-alpha1-antitrypsin complexes, matrix metalloproteinase 9, cystatin C, plasmin-antiplasmin complexes and tissue plasminogen activator, have been correlated with AAA progression and have biological plausibility. Although studies of these markers have shown promising results, they have not yet led to a clinically applicable biomarker. In future studies, adjustment for initial AAA size, smoking history and the measurement error for determination of AAA size, among other variables, should be taken into account. A large, prospective, standardized, follow-up study will be needed to investigate multiple circulating biomarkers for their potential role in the prediction of AAA progression, followed by a study to investigate the effect of treatment on the circulating levels of biomarkers.
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PMID:Biomarkers of AAA progression. Part 1: extracellular matrix degeneration. 1946 92