New Insights into the Inhibition of Human Neutrophil Elastase by Heparin † (original) (raw)
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The Journal of biological chemistry, 1991
Heparin depresses the second-order rate constant ka for the inhibition of neutrophil elastase by alpha 1-proteinase inhibitor. High molecular mass heparin decreases ka from 1.3 x 10(7) M-1 s-1 to a limit of 4.6 x 10(4) M-1 s-1. Low molecular mass heparin is about 7-fold less effective. Dermatan sulfate and chondroitin sulfate are less efficient. Heparin preparations used in clinical care also strongly depress ka when tested at concentrations corresponding to their clinical efficacy. Heparin also decreases the ka for the elastase/eglin c and the cathepsin G/alpha 1-proteinase inhibitor systems but not that for the alpha 1-proteinase inhibitor/pancreatic elastase or trypsin pairs. These results, together with Sepharose-heparin binding studies, indicate that the ka-depressing effect of the polymer is related to its ability to form a tight complex with elastase but not with alpha 1-proteinase inhibitor. One mol of high molecular mass heparin binds 3 mol of neutrophil elastase with a Kd ...
Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends
Medicines, 2019
The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality...
Multiple Functional Domains of the Heparin Molecule
Proceedings of The National Academy of Sciences, 1981
Affinity-fractionated porcine heparin was randomly scissioned by chemical techniques to give hexasaccharides, octasaccharides, decasaccharides, and mucopolysaccharide fragments of ≈ 14 residues and ≈ 16 residues that were able to complex with the protease inhibitor. Direct measurements of the kinetic behavior of the hexasaccharides, octasaccharides, and decasaccharides showed that these fractions greatly enhanced the rate of Factor Xa inactivation by antithrombin. Indeed, these species exhibited specific molar activities that ranged from 6.9% (hexasaccharide) to 60.9% (decasaccharide) of that of the heparin fragment of ≈ 16 residues. However, these oligosaccharides exhibited essentially no ability to accelerate thrombin-antithrombin interactions. The avidity of the hexasaccharides, octasaccharides, and decasaccharides for the protease inhibitor increased as function of size with the respective dissociation constants ranging from 5.5× 10-6 M to 2.9× 10-7 M. These data suggest that the region of the heparin molecule needed for catalyzing Factor Xa-antithrombin interaction is intimately related to the antithrombin binding domain. The smallest complex carbohydrate fragment that accelerated the inactivation of thrombin by antithrombin had ≈ 14 residues. This fraction had an avidity for the protease inhibitor of 2.8× 10-7 M and specific molar activities of 140 units per μ mol (thrombin neutralization) and 460 units per μ mol (factor Xa inactivation). The largest heparin fragment examined contained ≈ 16 residues. This fraction had an avidity for antithrombin of 2.4× 10-7 M and specific molar activities of 500 units per μ mol (thrombin neutralization) and 560 units per μ mol (Factor Xa inactivation). Detailed kinetic analyses showed that these two species are able to directly activate antithrombin to the same extent with respect to thrombin inhibition. However, the larger mucopolysaccharide fragment is also capable of approximating free enzyme with protease inhibitor.