Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of four human serine proteinases on the human cysteine proteinase inhibitor, cystatin C, has been studied in vitro. Neutrophil elastase in catalytic amounts was observed to rapidly cleave cystatin C at neutral pH, thereby giving rise to a modified form of the inhibitor lacking the N-terminal Ser1-Val10 decapeptide. The two other leukocyte serine proteinases, cathepsin G and neutrophil proteinase 4, did not catalytically hydrolyse cystatin C bonds. Neither had the seminal plasma serine proteinase, prostate-specific antigen, any effect on cystatin C. The physiological implications of neutrophil elastase catalysed modification of cystatin C are discussed, and recent findings indicating that this reaction also occurs in vivo are reviewed.
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PMID:Regulation of cystatin C activity by serine proteinases. 180 27

Recent studies have shown that the bovine cysteine proteinase inhibitor, cystatin C, is synthesized as a preprotein containing a 118-residue mature protein. However, the forms of the inhibitor isolated previously from bovine tissues had shorter N-terminal regions than expected from these results, and also lower affinity for proteinases than human cystatin C. In this work, we report the properties of recombinant, full-length bovine cystatin C having a complete N-terminal region. The general characteristics of this form of the inhibitor, as reflected by the isoelectric point, the far-ultraviolet circular dichroism spectrum, the thermal stability and the changes of tryptophan fluorescence on interaction with papain, resembled those of human cystatin C. The affinity and kinetics of inhibition of papain and cathepsins B, H and L by the bovine inhibitor were also comparable with those of the human inhibitor, although certain differences were apparent. Notably, the affinity of bovine cystatin C for cathepsin H was somewhat weaker than that of human cystatin C, and bovine cystatin C bound to cathepsin L with about a four-fold higher association rate constant than the human inhibitor. This rate constant is comparable with the highest values reported previously for cystatin-cysteine proteinase reactions. The full-length, recombinant bovine cystatin C bound appreciably more tightly to proteinases than the shorter form characterized previously. Digestion of the recombinant inhibitor with neutrophil elastase resulted in forms with truncated N-terminal regions and appreciably decreased affinity for papain, consistent with the forms of bovine cystatin C isolated previously having arisen by proteolytic cleavage of a mature, full-length inhibitor.
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PMID:The affinity and kinetics of inhibition of cysteine proteinases by intact recombinant bovine cystatin C. 1036 30

Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution Leu68-->Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is N-terminally truncated by 10 amino acids. To elucidate the role of the N-terminal truncation for protein stability and aggregation properties, (delta1-10,L68Q)-cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wild-type cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (delta1-10,L68Q)-cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of full-length L68Q cystatin C. No evidence was found that the N-terminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients' amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the N-terminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the N-terminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higher-order aggregation. We conclude that the N-terminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.
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PMID:Physico-chemical properties of the N-terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients. 1193 68

Several BPTI-Kunitz-type serine proteinase inhibitors were described in tick Boophilus microplus and Rhipicephalus sanguineus species. In this work, we present a synthetic gene based on two tick BPTI-Kunitz-type serine proteinase inhibitors, the first domain of B. microplus trypsin inhibitor-A (BmTI-A) and the carrapatin, the inhibitors were named BmTIsint and BmTIsint Mut. Our present results showed that BmTIsint and BmTIsint Mut inhibited trypsin (K(i) 3.3 and 1.0 nM) and human plasma kallikrein (K(i) 16.5 and 35 nM), but in contrast to BmTI-A, the inhibitors did not inhibit human neutrophil elastase. BmTIsint was able to produce immunological response in mice but not in bovines. In addition, it is the first description of a BPTI-Kunitz-type inhibitor as a cysteine proteinase inhibitor, BmTIsint apparent dissociation constant (K(i)) for cathepsin L was 108 nM. Our findings open the possibility up to obtain new molecules as potent serine or cysteine proteinase inhibitors using BmTIsint as a model.
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PMID:An unexpected inhibitory activity of Kunitz-type serine proteinase inhibitor derived from Boophilus microplus trypsin inhibitor on cathepsin L. 1641 23