Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.1 (chymotrypsin)
10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By exploiting its capacity for binding to DNA, the protease inhibitor alpha 1-antichymotrypsin has been isolated from human serum by ammonium sulfate fractionation and successive chromatography on QAE-Sephadex, DNA-cellulose, and Sephacryl S-300. This experimental procedure compares favorably with existing methods for preparing alpha 1-antichymotrypsin in terms of overall yield and practical convenience. The purified alpha 1-antichymotrypsin was homogeneous as judged by electrophoretic and immunoelectrophoretic criteria. From its inhibition of the fluorimetric titration of chymotrypsin with 4-methylumbelliferyl-p-trimethylammonium cinnamate it was shown to combine with chymotrypsin in a 1:1 molar ratio and thus to retain its biological activity.
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PMID:The purification of alpha 1-antichymotrypsin from human serum using DNA-cellulose chromatography. 668 10

Human alpha 1-antichymotrypsin was purified from human pleural fluid and from human serum. Four affinity chromatographic steps were required to obtain pure alpha 1-antichymotrypsin. Pleural and serum alpha 1-antichymotrypsin have the same molecular weight, which was estimated by SDS-polyacrylamide gel electrophoresis to be 58 000. The chemical composition of the two types of alpha 1-antichymotrypsin is the same. Using a technique for visualization of the chymotrypsin inhibitors, we showed that the pure alpha 1-antichymotrypsin obtained from the two physiological fluids had its inhibitory capacity preserved.
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PMID:Purification and characterization of alpha 1-antichymotrypsin from human pleural fluid and human serum. 689 51

A tissue culture line of a human malignant melanoma, SEKI, induced cachexia in nude mice (BALB/c-nu/nu) (Kondo et al., Cancer Res., 41: 2912-2916, 1981). During the investigation of the cause of the cachexia, the melanoma was found to produce a protein immunologically identical to human alpha 1-antichymotrypsin (alpha 1-Ach). Tissues of the SEKI melanoma contained the protein immunologically equivalent to 0.29 +/- 0.11 (S.D.) mg of human alpha 1-Ach per g of wet tissue, while the other six human malignant tumors transplanted into nude mice did not contain a detectable amount of it. In the serum of nude mice bearing the melanoma, this protein appeared soon after the tumor growth occurred and gradually increased up to the level equivalent to 5 mg of human alpha 1-Ach per dl. Removal of the tumor resulted in a rapid decrease of the protein in the serum to an undetectable level within 1 day. This problem was never detected in the serum of nude mice bearing the other 27 human malignant tumors or controls. Purification of this protein was carried out by the column chromatography using DE-52, Blue-Sepharose, and SP-Sephadex. The elution patterns were the same as those of alpha 1-Ach in human serum, and the molecular weight of the protein was estimated as 69,000 by Sephadex G-100 column chromatography and 65,000 by polyacrylamide gel electrophoresis with sodium dodecyl sulfate. This purified protein, however, did not exhibit inhibitory activity against chymotrypsin. These results show that this melanoma produced a protein immunologically identical and physicochemically very similar to human alpha 1-Ach. This melanoma-nude mouse system may provide a useful model for investigating the synthesis of human alpha 1-Ach and analysis of its physiological roles.
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PMID:Production of human alpha 1-antichymotrypsin-like protein by a human malignant melanoma transplanted into nude mice. 689 63

Protease inhibitors and protease (caseinolytic, elastinolytic and esterolytic) activity were analysed in 190 milk samples from 94 mothers from day 1 to day 160 after delivery. The main protease inhibitors in human milk are alpha 1-antichymotrypsin and alpha 1-antitrypsin. As measured by electroimmunoassay, the level of alpha 1-antichymotrypsin in day 1 colostrum was higher than that in normal serum. Trace amounts of inter-alpha-trypsin inhibitor, alpha 2-antiplasmin, alpha 2-macroglobulin, antithrombin III, or antileukoprotease could be demonstrated. According to their protease inhibiting activity, the 53 milk samples from day 1-3 could be divided into two groups. (1) Presence of protease inhibiting activity (n = 35). Both alpha 1-antitrypsin and alpha 1-antichymotrypsin appeared intact and were able to form complexes with added trypsin or chymotrypsin although the major part of alpha 1-antichymotrypsin showed a retarded electrophoretic mobility. The proteolytic inhibiting activity, in spite of the presence of immunoreactive inhibitors (n = 18). alpha 1-antichymotrypsin had a precipitate pattern similar to group 1, whereas alpha 1-antitrypsin had a major fraction with slightly retarded mobility and two minor peaks in the alpha 1-and beta-regions. These precipitate patterns were unchanged on addition of human trypsin or chymotrypsin compatible with the presence of nonreactive inhibitor only. These samples had a caseinolytic and esterolytic activity with an electrophoretic mobility in the beta-region. All samples from day 4 and later had a demonstrable protease inhibiting activity.
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PMID:Protease inhibitors and their relation to protease activity in human milk. 704 31

PSA is a 34-kDa 240-amino-acid glycoprotein produced exclusively by prostatic epithelial cells. PSA is a serine protease, is a member of the kallikrein gene family, and has a high sequence homology with human glandular kallikrein. It has chymotrypsin-, trypsin-, and esterase-like activities. In the serum it is present mainly in a complex form with alpha 1-antichymotrypsin. It is secreted in the seminal plasma and is responsible for liquefaction of the seminal coagulum. The production of PSA proteins appears to be under the control of circulating androgens acting through the androgen receptors. The PSA gene is up-regulated predominantly by androgens at both the protein and mRNA levels. DRE causes minimal changes in the PSA level, while prostate massage, ultrasonography, systoscopic examination, and prostate biopsy can all cause clinically significant elevations. Other conditions, such as prostatitis, prostate intraepithelial neoplasia, acute urinary retention, and renal failure can also elevate the PSA level. The value of PSA as a screening tool is questionable because of the great deal of overlap in PSA levels between BPH and prostate cancer. However, if used in men over 50, in conjunction with DRE and/or ultrasonography, it may become a vital part of the early detection program. PSA's role in determining the clinical and pathological stage is also limited, in spite of the direct correlation between the pathological stage and the PSA level, because of great overlap in the PSA levels in various stages. The most important clinical utility of PSA is in monitoring patients after definitive therapy. PSA is most sensitive and reliable in the detection of a residual tumor, possibly recurrence, or disease progression following treatment, irrespective of the treatment modality. PSA can accurately predict the tumor status and can detect recurrence several months before its detection by any other method. PSA is also a very sensitive and specific immunohistochemical marker for tumors of prostatic origin. Compared to PAP, PSA is a more precise and meaningful marker in all clinical situations. With the development of ultrasensitive assays and the adoption of an international standard PSA calibrator, so that results from multicenter studies can be compared, PSA could become one of the most useful tumor marker in cancer biology.
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PMID:Prostatic specific antigen. 753 74

Prostate-specific antigen (PSA) is a tissue-specific serine protease similar in structure to the trypsin-like glandular kallikreins but which is unique inasmuch as the enzyme activity is similar to that of chymotrypsin. The active enzyme is a single chain glycoprotein of 237 amino acids. The major form of PSA in serum is complexed to alpha 1-antichymotrypsin (ACT). A small amount is free, non-complexed despite a large excess of ACT. This suggests that the form in serum lacks enzyme activity. Although serum PSA concentrations are regularly abnormally high (above 4 micrograms/L) in prostate cancer (CAP), the utility of PSA measurements in the early detection of CAP is limited, as many tumors are undetected at a cut-off of 4 micrograms/L. Also, 25% of all men with benign prostate hyperplasia (BPH) have serum PSA levels above 4 micrograms/L. Using assays specially developed to measure free and complexed forms of PSA in serum, we found the proportion of PSA-ACT complexes to be higher in CAP than in BPH, but the ratio of free-to-total PSA in serum to be lower. Using an abnormally low ratio of free-to-total PSA to detect CAP increases diagnostic specificity by 15 to 20%, compared to using a high serum PSA concentration. This suggests that the ratios of free-to-total PSA significantly increase the ability to distinguish BPH from localized CAP. The molecular basis is unclear, but may be related to the high incidence of prostate tumor cells producing both PSA and ACT. This is in contrast to the lack of ACT production in BPH epithelium. Possibly owing to lack of ACT production in BPH areas, conditions are not optimal for complex formation, whereas tumors producing both ACT and PSA may promote the formation of PSA-ACT complexes in CAP.
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PMID:Regulation of the enzymatic activity of prostate-specific antigen and its reactions with extracellular protease inhibitors in prostate cancer. 754 78

Neutrophil chemotaxis plays an important role in the inflammatory response and when excessive or persistent may augment tissue damage. The effects of inhibitors indicated the involvement of one or more serine proteinases in human neutrophil migration and shape change in response to a chemoattractant. Monospecific antibodies, chloromethylketone inhibitors, and reactive-site mutants of alpha 1-antitrypsin and alpha 1-antichymotrypsin were used to probe the specificity of the proteinases involved in chemotaxis. Antibodies specific for cathepsin G inhibited chemotaxis. Moreover, rapid inhibitors of cathepsin G and alpha-chymotrypsin suppressed neutrophil chemotaxis to the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and zymosan-activated serum in multiple blind well assays and to fMLP in migration assays under agarose. The concentrations of antichymotrypsin mutants that reduced chemotaxis by 50% would inactivate free cathepsin G with a half-life of 1.5-3 s, whereas the concentrations of chloromethylketones required to produce a similar inhibition of chemotaxis would inactivate cathepsin G with a half-life of 345 s. These data suggest different modes of action for these two classes of inhibitors. Indeed the chloromethylketone inhibitors of cathepsin G (Z-Gly-Leu-Phe-CMK) and to a lesser extent of chymotrypsin (Cbz-Gly-Gly-Phe-CMK) mediated their effect by preventing a shape change in the purified neutrophils exposed to fMLP. Antichymotrypsin did not affect shape change in response to fMLP even at concentrations that were able to reduce neutrophil chemotaxis by 50%. These results support the involvement of cell surface proteinases in the control of cell migration and show that antichymotrypsin and chloromethylketones have differing modes of action. This opens the possibility for the rational design of anti-inflammatory agents targeted at neutrophil membrane enzymes.
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PMID:The control of neutrophil chemotaxis by inhibitors of cathepsin G and chymotrypsin. 755 4

The brain of Alzheimer disease patients contains plaques that are diagnostic for the disease. The plaques also contain beta-amyloid peptide, alpha 1-antichymotrypsin, and the element aluminum. We present indirect evidence that can relate all three components of plaques to each other in such a way as to suggest their involvement in the etiology of the disease. The beta-amyloid peptide is derived by proteolytic processing from beta-amyloid precursor proteins and some of these proteins contain a domain that is highly homologous to bovine pancreatic trypsin inhibitor. Bovine pancreatic trypsin inhibitor also inhibits alpha-chymotrypsin and we show that aluminum affects both the activity and the inhibition of this enzyme. At pH 6.5, in the presence of aluminum, the enzyme activity is doubled, and the inhibitor is only 1% as effective as in the absence of the metal ion. The inhibition by BX-9, a protease inhibitor prepared from protein components of amyloid plaques, is also reduced by aluminum; so too is that by alpha 1-antichymotrypsin but to a lesser degree. In the Alzheimer brain, we propose that aluminum may accelerate proteolytic processing of the beta-amyloid precursor protein by suppression of the inhibitor domain. Thus, the beta-amyloid peptide may accumulate and initiate plaque formation.
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PMID:Regulation of serine protease activity by aluminum: implications for Alzheimer disease. 767 14

The interactions of bovine pancreatic chymotrypsin (Chtr) and recombinant alpha 1-antichymotrypsin (rACT) and rACT variants were studied by kinetic and gel electrophoretic analyses, leading to the formulation of a general kinetic scheme that accounts for all known results concerning this serpin-protease pair, as well as for results obtained with other such pairs. Incubation of rACT and Chtr leads rapidly to the formation of an inhibited complex, Chtr.rACT*, that is stable toward sodium dodecyl sulfate denaturation and boiling. The extent of release of active Chtr from this complex increases markedly as ionic strength, mu, is raised. The kinetic scheme quantitatively accounts for this effect on the basis of a partitioning of Chtr.rACT* between dissociation of the complex to yield active enzyme and cleaved rACT, and Chtr-catalyzed conversion of the complex to a form that is much more resistant to release of active enzyme. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses of reaction mixtures of rACT and Chtr are consistent with the scheme. Also consistent are the results of experiments measuring the effects of 1) Chtr.rACT* concentration, 2) uncomplexed Chtr, and 3) added alpha 2-macroglobulin on active Chtr release from Chtr.rACT*. Proteolysis of Chtr.rACT* to give a resistant complex is also catalyzed by human neutrophil elastase, a process with potential physiological relevance. Comparison of the rates of Chtr dissociation from the complexes formed with rACT and with rACT variants mutated at the P1 site suggests that such rates are more sensitive to P1 substitution at low mu than at high mu. Several equivalents of the L358R-rACT variant are required for full inhibition of Chtr. This observation is also quantitatively accounted for by the proposed kinetic scheme, on the basis of another partitioning step between L358R-rACT acting as a substrate or as an inhibitor toward Chtr.
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PMID:Antichymotrypsin interaction with chymotrypsin. Partitioning of the complex. 769 93

alpha 1-Antichymotrypsin, a member of the serpin family of serine proteinase inhibitors, has been reported to inhibit chymotrypsin by a modified version of the suicide substrate reaction mechanism operative for other serpins. To investigate if this mechanism is also applicable to the inhibition of cathepsin G by this serpin, the effect of temperature on the reaction between cathepsin G and alpha 1-antichymotrypsin has been examined by SDS-PAGE and stoichiometric titrations. At 0 degree C, a cathepsin G-alpha 1-antichymotrypsin complex of M(r) 89,250 is formed which, at 38 degrees C, was cleaved by free enzyme to give a stable complex of M(r) 80,250. The reaction stoichiometry at 0 degree C was 1.53, which decreased to 1.30 at 38 degrees C, consistent with an decrease in the substrate pathway. These data are compatible with the modified suicide substrate reaction scheme. The formation of three products (cleaved inhibitor and two forms of complex) from the reaction and the potential for differential product formation suggests that modulation of the suicide substrate mechanism may play a role in the regulation of inflammatory processes mediated by cathepsin G.
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PMID:Studies on inhibition of neutrophil cathepsin G by alpha 1-antichymotrypsin. 770 88


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