Inhibition of human elastase from polymorphonuclear leucocytes by a glycosaminoglycan polysulfate (Arteparon®)

Baici, Antonio; Salgam, Prathima; Fehr, K; Böni, A

doi:10.1016/0006-2952(80)90131-8

Cited by 85 publications

(44 citation statements)

References 7 publications

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“…Sulfated glycosaminoglycans prevent NE-induced lung emphysema in animal models (31,33). These ligands are partial inhibitors of the elastolytic activity of NE (27,34,35). Suramin, which fully inhibits elastolysis and has already been used in human cancer therapy (5)(6)(7)(8) should therefore prove to be an efficient drug in diseases characterized by massive neutrophil recruitment and activation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophil Serine Proteinases by Suramin

Cadène

Duranton

North

et al. 1997

Journal of Biological Chemistry

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Suramin, a hexasulfonated naphtylurea recently used as an anti-tumor drug, is a potent inhibitor of human neutrophil elastase, cathepsin G, and proteinase 3. The complexes it forms with these enzymes are partially active on synthetic substrates, but full inhibition takes place when elastase activity is measured with fibrous elastin or when cathepsin G activity is measured using platelet aggregation. One molecule of elastase binds four molecules of suramin with a K i of 2 ؋ 10 ؊7 M as determined by enzyme inhibition or intrinsic fluorescence enhancement of suramin. The binding curves show no sign of cooperativity or anticooperativity. The K i for the complexes with cathepsin G and proteinase 3 are 8 ؋ 10 ؊8 and 5 ؋ 10 ؊7 M, respectively. Ionic strength increases the K i of the elastase-suramin complex in a way that suggests that four of the six sulfonate groups of suramin form ionic interactions with basic residues of the enzyme and that at saturation almost all arginines of elastase form salt bridges with suramin. The neutrophil proteinase-inhibitory activity of suramin might be used to prevent tissue destruction and thrombus formation in diseases where massive infiltration and activation of neutrophils take place.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophil Serine Proteinases by Suramin

Cadène

Duranton

North

et al. 1997

Journal of Biological Chemistry

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“…The inhibition of human leukocyte elastase by a glycosaminoglycan polysulfate has been described as hyperbolic uncompetitive [6]. The kinetic mechanism of this enzyme with different substrates has been also reported [7].…”

Section: Analysis Of Two Real Casesmentioning

confidence: 99%

“…However, a glycosaminoglycan polysulfate fraction with a molecular weight of 2100 showed a Ki large enough to allow analysis with the specific velocity plot. Whilc all details are reported elsewhere [6], results dealing with this particular example are shown in Fig. 6.…”

Section: Analysis Of Two Real Casesmentioning

confidence: 99%

The Specific Velocity Plot

Baici¹

1981

European Journal of Biochemistry

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A new method is described for plotting kinetic results for inhibited enzymatic reactions. The plot is particularly designed for the analysis of hyperbolic, mixed-type inhibitors, but can be applied to any other linear system. The method consists of plotting experimental data in a normalized way, as ~i~/ t '~ versus the specific vclocity ./(I + n), where c~/ c i represents the ratio of the initial velocities for the non-inhibited and inhibited reactions at a given substrate concentration [S], and F is the [S]/K,,, ratio. The procedure provides a simple way of determining the inhibition constants Ki and Ki. i.e. the dissociation constants of the EI and ESI complexes, respectively, and the velocity saturation values.An enzyme inhibitor, I, is classified as linear or hyperbolic depending on the shape of a reciprocal velocity versus [I] plot. I will be called a linear or hyperbolic inhibitor depending on this plot (or similar plots) bcing a straight line or a hyperbola, respectively. In other words, a linear inhibitor will drive the enzymatic velocity to zero under saturating conditions, whereas in a hyperbolic system an infinitely high [I] will convert the enzyme to a modified, but still functional complex, ESI, with a decreased rate of product formation.The analysis of linear systems can be done using a variety of plotting methods [I], and an excellent combination is the concomitant use of the Dixon [2] and Cornish-Bowden plots [3]. These two plots, used together, will distinguish between all four types of simple linear inhibition, i.e. competitive, uncompetitive, noncompetitive and mixed inhibition. For hyperbolic inhibitors, the calculation of inhibition parameters can be performed with the aid of particular The present report describes an alternative way to analyze enzyme inhibition, that can be used either alone or as a complementary method to other techniques. The specific velocity plot reported here is always linear, whether the inhibitor is linear or hyperbolic, mixed type or not. By simple inspection of the plot it is possible to see whether the dissociation constants of the El and ESI complexes are equal or different. Simple replots permit the calculation of all parameters needed.

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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%

“…A variety of combinations of monosaccharides, different type of linkages, and branch formation as well as secondary modifications such as sulfation, phosphorylation, methylation, and acetylation visualize the unusual complexity of these sugar chains, which when covalently attached to proteins in proteoglycans carry a large body of biological information (38, 60 -62). The interactions between GAGs and lysosomal enzymes are electrostatic in nature (50,51); however, the molecular mechanisms responsible for the effect of GAGs on activation and activity of lysosomal hydrolases are still not entirely clear.…”

Section: Figmentioning

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 human elastase from polymorphonuclear leucocytes by a glycosaminoglycan polysulfate (Arteparon®)

Cited by 85 publications

References 7 publications

Inhibition of Neutrophil Serine Proteinases by Suramin

Inhibition of Neutrophil Serine Proteinases by Suramin

The Specific Velocity Plot

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

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