Inhibition of the human leukocyte endopeptidases elastase and cathepsin G and of porcine pancreatic elastase by N-oleoyl derivatives of heparin

Baici, Antonio; Diczházi, Csaba; Neszmélyi, András; Móczár, E.; Hornebeck, William

doi:10.1016/0006-2952(93)90321-m

Cited by 42 publications

(32 citation statements)

References 32 publications

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“…Such a mechanism was already described concerning inhibition of elastase and cathepsin G by heparin (32). The plasmin inhibition data could be satisfactorily fitted to Equation 3, which assumes that the inhibition potency depends on the binding stoichiometry (n), the equilibrium dissociation constant (K i ), and the dimensionless numbers ␣ and ␤.…”

Section: Discussionmentioning

confidence: 79%

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Ledoux

Papy-García

Escartin

et al. 2000

Journal of Biological Chemistry

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Some synthetic dextran derivatives that mimic the action of heparin/heparan sulfate were shown to promote in vivo tissue repair when added alone to wounds. These biofunctional mimetics were therefore designated as "regenerating agents" in regard to their in vivo properties. In vitro, these biopolymers were able to protect various heparin-binding growth factors against proteolytic degradation as well as to inhibit the enzymatic activity of neutrophil elastase. In the present work, different dextran derivatives were tested for their capacity to inhibit the enzymatic activity of human plasmin. We show that dextran containing carboxymethyl, sulfate as well as benzylamide groups (RG1192 compound), was the most efficient inhibitor of plasmin amidolytic activity. The inhibition of plasmin by RG1192 can be classified as tight binding hyperbolic noncompetitive. One molecule of RG1192 bound 20 molecules of plasmin with a K i of 2.8 ؋ 10 ؊8 M. Analysis with an optical biosensor confirmed the high affinity of RG1192 for plasmin and revealed that this polymer equally binds plasminogen with a similar affinity (K d ‫؍‬ 3 ؋ 10 ؊8 M). Competitive experiments carried out with 6-aminohexanoic acid and kringle proteolytic fragments identified the lysine-binding site domains of plasmin as the RG1192 binding sites. In addition, RG1192 blocked the generation of plasmin from Glu-plasminogen and inhibited the plasmin-mediated proteolysis of fibronectin and laminin. Data from the present in vitro investigation thus indicated that specific dextran derivatives can contribute to the regulation of plasmin activity by impeding the plasmin generation, as a result of their binding to plasminogen and also by directly affecting the catalytic activity of the enzyme.

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Section: Discussionmentioning

confidence: 79%

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Ledoux

Papy-García

Escartin

et al. 2000

Journal of Biological Chemistry

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“…Heparin is a noncompetitive inhibitor of elastase [21 ] and also decreases the rate of inhibition of elastase by cti-protease inhibitor without altering the sta bility of the irreversible elastase inhibitor complex [22], Therefore, the administration of heparin could have de creased EIC levels in our patients. Our data, however, do not support such a hypothesis, since patients treated with heparin before venipuncture did not show lower EIC lev els than patients without prior heparin administration.…”

Section: Discussionmentioning

confidence: 84%

Increased Levels of Leukocyte Elastase in Ischemic Stroke and in Subjects with Vascular Risk Factors

et al. 1995

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Proteolytic enzymes by polymorphonuclear leukocytes such as elastase may contribute to the pathogenesis of acute cerebral ischemia. We measured elastase α₁-protease inhibitor complexes (EIC) in acute ischemic stroke and in controls with and without vascular risk factors. Levels of EIC were higher in patients (n = 24, 51.4 ± 18.5 ng/ml) than in healthy controls (n = 26, 36.2 ± 11.5 ng/ml, p < 0.001) but not higher than in controls with risk factors (n = 22, 53.4 ± 29.6 ng/ml). Stroke patients with recent or concomitant infections had higher EIC levels than all other groups (n = 14, 71.0 ± 24.6 ng/ml). This result suggests leukocyte activation in acute stroke and in subjects with increased risk for stroke.

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“…Inhibition of the activity of numerous lysosomal hydrolases by GAGs in vitro is well documented (50 -56). For human leukocyte elastase and cathepsin G, the inhibition was classified as tight-binding, hyperbolic, and noncompetitive (51,52,54,55). It required the presence of sulfated groups and inversely depended upon the chain length of oligosaccharides (51,52,54,57,58).…”

Section: Discussionmentioning

confidence: 99%

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Golabek

Walus

Wisniewski

et al. 2005

Journal of Biological Chemistry

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Tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of polypeptides and shows a minor endoprotease activity. Mutations in TPP I lead to classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease. TPP I proenzyme is converted in lysosomes into a mature enzyme with the assistance of another protease and is able to autoactivate in acidic pH in vitro via a unimolecular mechanism. Because autoactivation in vitro at the pH values reported for lysosomes generated inactive enzyme, we intended to determine whether physiologically relevant factors can modify this process to also make it plausible in vivo. Here, we report that high ionic strength and glycosaminoglycans (GAGs) increase yields (ionic strength) or yields and rates (GAGs) of activation, enhance degradation of liberated TPP I prosegment fragments, and switch effective autoactivation of TPP I proenzyme toward less acidic pH values (up to pH 6.0). Although ionic strength and GAGs also inhibited TPP I activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appears to be of rather limited functional significance. Importantly, binding to GAGs improved thermal stability of TPP I and protected the enzyme against alkaline pH-induced denaturation in vitro (t1 ⁄2 of mature enzyme at pH 7.4 increased by ϳ8-fold in the presence of heparin) and in vivo (ϳ2-fold higher loss of TPP I in cells deficient in GAGs than in control cells after bafilomycin A1 treatment). These findings elucidate a potent physiologically relevant mechanism of TPP I regulation by GAGs and suggest that generation of the active enzyme via autoactivation can be accomplished not only in vitro but in vivo as well.

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Inhibition of the human leukocyte endopeptidases elastase and cathepsin G and of porcine pancreatic elastase by N-oleoyl derivatives of heparin

Cited by 42 publications

References 32 publications

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Increased Levels of Leukocyte Elastase in Ischemic Stroke and in Subjects with Vascular Risk Factors

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

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