Linked Life Data

9698370

Source:http://linkedlifedata.com/resource/pubmed/id/9698370

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
32
pubmed:dateCreated
1998-9-10
pubmed:abstractText
Uncontrolled proteolysis due to cathepsin G (cat G) may cause severe pathological disorders. Cat G is inhibited by alpha 1-antichymotrypsin (ACT) and alpha 1-proteinase inhibitor (alpha 1PI), two members of the serpin superfamily of proteins. To see whether these two inhibitors play a physiological proteolysis-preventing function, we have made a detailed kinetic investigation of their reaction with cat G. The kinetics of inhibition of cat G in the presence of inhibitor and substrate evidenced a two-step inhibition mechanism: E + I EI EI. The cat G/ACT interaction is described by Ki = 6.2 x 10(-)8 M and k2 = 2.8 x 10(-)2 s-1, while the cat G/alpha 1PI association is governed by Ki = 8.1 x 10(-)7 M and k2 = 5.5 x 10(-)2 s-1. The reliability of these kinetic constants was checked using a number of experiments which all gave consistent results: (i) both EI complexes were found to be enzymatically inactive, (ii) the Ki values were determined directly using initial velocity experiments of cat G-catalyzed hydrolysis of substrate in the presence of inhibitor, (iii) the second-order rate constants k2/Ki were measured using second-order inhibition experiments in the absence of substrate, and (iv) the ratio of the two second-order rate constants was determined by measuring the partition of cat G between the two fluorescently labeled serpins. Since the plasma concentrations of ACT and alpha 1PI are much higher than their Ki values, cat G released from neutrophils will be fully taken up as rapidly forming EI complexes, that is, 70% with ACT and 30% with alpha 1PI. Both ACT and alpha 1PI are thus physiological cat G inhibitors whose inhibitory potential does not depend on the formation of the stable inhibitory species EI characteristic of serpins. Such an in vivo inhibition mechanism might take place with other serpin/proteinase systems.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
11239-45
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Kinetic mechanism of the inhibition of cathepsin G by alpha 1-antichymotrypsin and alpha 1-proteinase inhibitor.
pubmed:affiliation
Laboratoire d'Enzymologie, INSERM U 392, Université Louis Pasteur de Strasbourg, France.
pubmed:publicationType
Journal Article