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)

The primary subsite specificities of human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin A alpha, and the protease from strain V-8 of Staphylococcus aureus have been mapped with a series of tripeptide thiobenzyl ester substrates of the general formula Boc-Ala-Ala-AA-SBzl, where AA represents one of 13 amino acids. In addition, the effects of a P2 Pro and P4 methoxysuccinyl and succinyl groups were investigated. In an attempt to introduce specificity and/or reactivity into the substrate Boc-Ala-Ala-Leu-SBzl(X), the 4-chloro-, 4-nitro-, and 4-methoxythiobenzyl ester derivatives were studied. Enzymatic hydrolyses of the substrates were measured in the presence of 4,4'-dithiobis(pyridine) or 5,5'-dithiobis(2-nitrobenzoic acid), which provided a highly sensitive assay method for free thiol. The thio esters were excellent substrates for the enzymes tested, and in many cases, the best substrates reported here have kcat/KM values higher than those reported previously. The best substrate for human leukocyte elastase was Boc-Ala-Pro-Nva-SBzl(Cl), which has a kcat/KM of 130 X 10(6) M-1 s-1. A very reactive rat mast cell protease substrate, Boc-Ala-Ala-Leu-SBzl(NO2), was also found. The S. aureus V-8 protease was the most specific enzyme tested since it hydrolyzed only Boc-Ala-Ala-Glu-SBzl. Substituents on the thiobenzyl ester moiety of Boc-Ala-Ala-Leu-SBzl resulted in decreased KM values with human leukocyte elastase and rat mast cell protease I when compared to the unsubstituted derivative.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II. Bovine chymotrypsin A alpha, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates. 638 May 80

Several a-pyrones have been synthesized and investigated for their in vitro inhibitory activity using a-chymotrypsin (a-CT), porcine pancreatic elastase (PPE) and human leukocyte elastase (HLE). 4-Hydroxy-6-undecyl-2H-pyran-2-one 4, 4-Hydroxy-6-[(1-butyl)heptyl]-2H-pyran-2-one 5 and 4-Methoxy-6-[(1-butyl) heptyl]-2H-pyran-2-one 6 were found to be specific inhibitors of HLE. These compounds constitute a promising new class of HLE inhibitors.
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PMID:Specific inhibition of human leukocyte elastase by substituted alpha-pyrones. 656 17

The N-acylsaccharins and N-acylbenzoisothiazolinones form a new class of acylating inhibitors of the serine proteases with a broad spectrum of activity. However, they are unique in that they are able to differentiate between various serine proteases because of the differential stability of the presumptive acyl-enzyme formed. Furoyl saccharin was the best studied among this class of inhibitors. We report evidence that the amide bond in the heterocyclic ring of this compound is cleaved by porcine pancreatic and human leukocyte elastases and chymotrypsin, forming acyl-enzymes. Radioisotope studies indicate that the saccharin portion of furoyl saccharin is attached to these enzymes in approximately a 1:1 molar ratio with enzyme, blocking the active site serine. The acylelastases thus prepared are unusually stable to hydrolysis, with kdeacyl values at neutral pH of 2.3 x 10(-6) s-1 for porcine pancreatic elastase and 1.4 x 10(-6) s-1 for human leukocyte elastase. Trypsin appears to be inhibited by a different mechanism. These data suggest a new approach to the design of specific synthetic protease inhibitors.
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PMID:Inhibition of elastase and other serine proteases by heterocyclic acylating agents. 677 4

Ozone decreased the trypsin, chymotrypsin, and elastase inhibitory activities of human alpha 1-proteinase inhibitor (alpha 1-PI) both in plasma and in solutions of the pure inhibitor. The total loss of porcine elastase inhibitory activity required 18 mol of ozone/mol of pure alpha 1-PI and approximately 850 mol of ozone/mol of alpha 1-PI in plasma. A corresponding loss of the ability to inhibit human leukocyte elastase was observed. Inactivated alpha 1-PI contains four residues of methionine sulfoxide, in addition to oxidized tyrosine and tryptophan. Electrophoretic analysis demonstrated that the ozone-inactivated alpha 1-PI did not form normal complexes witrh serine proteinases. These findings suggest that the inhalation of ozone could inactivate alpha 1-PI on the airspace side of the lung to create a localized alpha 1-PI deficiency, which might contribute to the development of emphysema.
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PMID:Ozone inactivation of human alpha 1-proteinase inhibitor. 690 14

A simple synthesis is described for 3-carboxypropionyl-Ala-Ala-Val-4-nitroanilide, a convenient and very specific substrate for human leukocyte elastase (Km = 1.0mM, kcat = 8.7 s-1). The substrate does not undergo appreciable spontaneous hydrolysis. It is not cleaved by trypsin or chymotrypsin and only rather slowly by porcine pancreatic elastase (Km = 9.1mM, kcat = 1.4 s-1).
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PMID:Synthesis and analytical use of 3-carboxypropionyl-alanyl-alanyl-valine-4-nitroanilide: a specific substrate for human leukocyte elastase. 690 47

Human leukocyte cathespin G strongly stimulates the rate of solubilization of human lung elastin by human leukocyte elastase. For instance, the elastolytic activity of an equimolar mixture of elastase and cathepsin G is more than 5 times higher than that of elastase alone. Optimal stimulation occurs only if cathepsin G and elastase act simultaneously on elastin. Potentiation of leukocyte elastase digestion of lung elastin may also be brought about by bovine alpha-chymotrypsin. This enzyme is about half as efficient as cathepsin G. Stimulation of leukocyte elastase activity by cathepsin G is about 3 times less pronounced with bovine ligamentum nuchae elastin than with human lung elastin. On the other hand, the elastolytic activity of porcine pancreatic elastase is only enhanced by 20 to 30% by cathepsin. Therefore, maximal potentiation of elastolysis occurs with the lung elastin/leukocyte elastase system. The pathologic relevance of these findings is discussed.
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PMID:Stimulation of the elastolytic activity of leukocyte elastase by leukocyte cathepsin G. 691 62

A number of N-arylbenzisothiazolinone 1,1-dioxides have been synthesized and examined for inhibitory activity against human leukocyte and porcine pancreatic elastase (EC 3.4.21.11), bovine alpha-chymotrypsin (EC 2.4.21.1), human leukocyte cathepsin G (EC 3.4.21.20), and bovine trypsin (EC 3.4.21.4). They are potent, selective, competitive inhibitors of human leukocyte elastase and chymotrypsin. The inhibitory capacity of these compounds is directly related to the electron-withdrawing capability of the aryl substituents. When sufficiently activated, the amide bond in the heterocyclic ring can be cleaved by the enzyme, resulting in inhibition which is highly specific. The most potent inhibitor of hummotrypsin. The inhibitory capacity of these compounds is directly related to the electron-withdrawing capability of the aryl substituents. When sufficiently activated, the amide bond in the heterocyclic ring can be cleaved by the enzyme, resulting in inhibition which is highly specific. The most potent inhibitor of human leukocyte elastase, the 2,4-dinitrophenyl derivative, has a Ki of 2.16 microM with elastase and 0.77 microM with chymotrypsin. This study demonstrates that it is possible to design specificity into non-peptide, low molecular weight serine protease inhibitors, which may have considerable pharmacologic potential.
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PMID:Selective inhibition of human leukocyte elastase and bovine alpha-chymotrypsin by novel heterocycles. 691 80

Complexes of alpha 1-antitrypsin with trypsin, alpha-chymotrypsin, and human leukocyte elastase were purified and examined for amino-terminal sequences. These complexes were shown to possess the expected N-terminal sequences for alpha 1-antitrypsin and the corresponding enzymes; no newly generated amino groups could be detected. Each of these three complexes was dissociated at pH 10, and the inhibitor component was isolated. When the latter was subjected to sodium dodecyl sulfate gel electrophoresis a single band was obtained in all cases, and its molecular weight was judged to be 45 000 compared to 52 000 for alpha 1-antitrypsin. Examination of the N-terminal sequence of these modified inhibitors, however, disclosed the presence of two molecular species with different N-termini. The predominant species had the N-terminal sequence previously reported for post-complex alpha 1-antitrypsin (Johnson, D. and Travis, J. (1978) J. Biol. Chem. 253, 7142-7144) and the same carboxyl sequence as alpha 1-antitrypsin. Present in lesser amounts was a species which had retained the same N-terminal sequence as alpha 1-antitrypsin, but of which the C-terminus was resistant to the action of carboxypeptidases A and B. From these results it is concluded that (1) alpha 1-antitrypsin is a double-headed inhibitor with identical but overlapping binding sites; (2) binding of the enzyme may occur at one of these two sites but not at both simultaneously, and (3) peptide cleavage does not occur as a consequence of the binding process but can be demonstrated only if the complex is dissociated.
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PMID:The interaction of alpha 1-antitrypsin with trypsin, chymotrypsin and human leukocyte elastase as revealed by end group analysis. 697 Nov 28

The association rate constants for the interaction of alpha-1-proteinase inhibitor, oxidized alpha-1-proteinase inhibitor, and alpha-1-antichymotrypsin with several mammalian serine proteinases have been determined. The results indicate that leukocyte elastase reacts more rapidly with alpha-1-proteinase inhibitor than any other proteinase tested, while leukocyte cathepsin G shows the strongest association with alpha-1-antichymotrypsin. Oxidation of the critical methionine residue of alpha-1-proteinase inhibitor reduces the association with leukocyte elastase by a factor of more than 2000 and also lowers the association with all of the other enzymes tested with the exception of chymotrypsin. Significantly, oxidation completely abolishes any interaction of alpha-1-proteinase inhibitor with porcine elastase, human plasmin or human thrombin. These data support previous results (Johnson, D., and Travis, J. (1979) J. Biol. Chem. 254, 4022-4026) which indicated that oxidation of human alpha-1-proteinase inhibitor in vivo could reduce the effectiveness of this inhibitor in controlling proteolysis. In the lung, in particular, oxidizing agents of both chemical and biological sources could, indirectly, augment elastolysis in this tissue, resulting in the development of pulmonary emphysema.
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PMID:Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. 698 30

Twenty-six novel peptidyl carbamates and thiocarbamates were synthesized and evaluated as elastase inhibitors. Eighteen compounds inhibited porcine pancreatic elastase, whereas only eleven of the newly synthesized compounds inhibited human leukocyte elastase. Neither of the other serine dependent proteases, trypsin or chymotrypsin, were affected by any of the active inhibitors. Structure-activity relationship studies indicated that inhibition was dependent on P1 and P'1 substitution as well as on the presence of the carbamate functionality. Placement of an isostere of valine at P1 and a 1-(phenyl mercaptotetrazole at P'1 resulted in the most active human leukocyte elastase inhibitor within this series of compounds (Ki - 3.0 x 10(-7) M).
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PMID:Peptidyl carbamates as novel elastase inhibitors: structure-activity relationship studies. 750 66


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