DNA strongly impairs the inhibition of cathepsin G by alpha(1)-antichymotrypsin and alpha(1)-proteinase inhibitor.
This paper explores the possibility that neutrophil-derived DNA interferes with the inhibition of neutrophil cathepsin G (cat G) and proteinase 3 by the lung antiproteinases alpha(1)-proteinase inhibitor (alpha(1)PI), alpha(1)-antichymotrypsin (ACT), and mucus proteinase inhibitor (MPI). A 30-base pair DNA fragment ((30bp)DNA), used as a model of DNA, tightly binds cat G (K(d), 8.5 nM) but does not react with proteinase 3, alpha(1)PI, ACT, and MPI at physiological ionic strength. The polynucleotide is a partial noncompetitive inhibitor of cat G whose K(i) is close to K(d). ACT and alpha(1)PI are slow binding inhibitors of the cat G-(30bp)DNA complex whose second-order rate constants of inhibition are 2300 M(-1) s(-1) and 21 M(-1) s(-1), respectively, which represents a 195-fold and a 3190-fold rate deceleration. DNA thus renders cat G virtually resistant to inhibition by these irreversible serpins. On the other hand, (30bp)DNA has little or no effect on the reversible inhibition of cat G by MPI or chymostatin or on the irreversible inhibition of cat G by carbobenzoxy-Gly-Leu-Phe-chloromethylketone. The polynucleotide neither inhibits proteinase 3 nor affects its rate of inhibition by alpha(1)PI. These findings suggest that cat G may cause lung tissue destruction despite the presence of antiproteinases.
Duranton
J
J
Laboratoire d'Enzymologie, INSERM Unité 392, Université Louis Pasteur de Strasbourg, F-67400 Illkirch, France.
Boudier
C
C
Belorgey
D
D
Mellet
P
P
Bieth
J G
JG
D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002846:Chromatography, Affinity; D004247:DNA / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D000514:alpha 1-Antichymotrypsin; D000515:alpha 1-Antitrypsin; D004247:DNA; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G