The Inhibition of Proteinases by Human α₁‐Antitrypsin

Abstract

The inhibition of human plasmin by a,-antitrypsin was time dependent and the rate of inhibition rapidly decreased with decreasing temperature.The effect of substrates on the inhibitions of trypsin and chymotrypsin was investigated. Theoretically the final degree of inhibition should be the same, whether the substrate is added to the proteinase-inhibitor system before or after the formation of the complex. The inhibition of chymotrypsin by a,-antitrypsin and of trypsin by commercial soybean trypsin inhibitor was in line with the prediction, with either casein or synthetic esters as substrates. However, in the trypsin-a,-antitrypsin system the degree of inhibition depended on the order in which the reactants were mixed. With both casein and p-tosyl-L-arginine methyl ester as substrates, inhibition was high when trypsin was preincubated with the inhibitor and the substrate was added later, and low or absent when the proteinase was added to the mixture of inhibitor and substrate.In the inhibition mixtures of plasmin, trypsin and chymotrypsin with a, -antitrypsin, distinct changes were detected by electrophoresis in polyacrylamide gel. The unreacted inhibitor diminished or disappeared and reaction products were formed at rates corresponding to rates of inhibition. a,-Antitrypsin, the most abundant proteinase inhibitor in human serum, exhibits a broad range of specificity toward proteinases. It is known to inhibit trypsin [I -41, chymotrypsin [2-41, elastase [3,5-81, plasmin [4,9-131, thrombin [4], collagenases [14,15] According to several authors the inhibition of trypsin and chymotrypsin by a,-antitrypsin is stoichiometric and is complete in a very short time [l -41. In contrast, the inhibition of kallikrein and plasmin is not strictly stoichiometric [4], is slow [3,4,10,11,16], and strongly temperature dependent [ 161. Acylation of a,-antitrypsin with maleic anhydride abolishes its trypsin-inhibiting capacity [ 19,201 suggesting that one or more lysine residues play a part in the binding process.Rimon et al. found that while inhibition of trypsin and chymotrypsin was not retarded in the presence of substrate, the inhbition of plasmin and thrombin was [4].I examined the reactions of plasmin, trypsin and chymotrypsin with a,-antitrypsin by inhibition studies. The effects of substrates on the inhibition of chymotrypsin were in good agreement with theoretical predictions, but on the inhibition of trypsin were not.The inhibition of the three different proteinases by a,-antitrypsin was accompanied by electrophoretically detectable changes, and the rate of these changes was about the same as the corresponding rate of inhibition.Some of these observations were included in a previous abstract [21].

Changes to the Human Serum Proteome in Response to High Intensity Interval Exercise: A Sequential Top-Down Proteomic Analysis

“…The increase in circulating protease inhibitors α-1-antichymotrypsin and α-1-antitrypsin and their pro-forms, and the binding protein fetuin-a, suggest a suppression of neutrophil, platelet and mast cell degranulation (Hercz, 1974; Lebreton et al, 1979). This may be a compensatory response to the observed HIIE-induced increase in circulating neutrophils (Neves et al, 2015).…”

Protease and antiprotease levels in blood of arthritic rats.

“…In particular, serum and synovial fluid levels of alpha1-antitrypsin and other antiproteases have been found to rise in patients with rheumatic disease (Brackertz et al, 1975). The most abundant antiprotease in plasma is alpha1-antitrypsin (Kueppers, 1971) and this protein has a broad specificity against proteases including many believed to be involved in inflammatory processes (Hercz, 1974).…”

The Purification and Properties of Human α1‐Antitrypsin (α1‐Antiprotease), Variant Z

“…It is conceivable that the net charges of the two proteins are different, but the segments of the molecules in which the corresponding difference is localised become eliminated from the complex through a proteolytic cleavage(s) in the interaction of the variants with the proteinase. There are indeed observations [37,46] indicating that x1 -antitrypsin is cleaved by trypsin in the course of the inhibition reaction, but this is less likely to take place with chymotrypsin [46]. However, an unconditional interpretation of these observations ( Fig.5 and 6) is subject to a better understanding of the interaction of al-antitrypsin with these proteases.…”