Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement.

Olson, Steven T.; Björk, Ingemar; Sheffer, Roberta; Craig, P.; Shore, Joseph D.; Choay, J

doi:10.1016/s0021-9258(18)42309-5

Cited by 457 publications

(297 citation statements)

References 48 publications

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“…Second, it facilitates PKa-FXII or FXIIa-FXII complex formation by bringing protease and substrate into proximity. This "template mechanism" 31,32 is also relevant to complex formation between FXIIa and its substrates PK and factor XI. 33 The goal of the present study was to investigate the contributions of FXII heavy chain domains (HCDs) to FXII activation, and FXIIa activation of PK.…”

Section: Discussionmentioning

confidence: 99%

Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains

et al. 2022

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Factor XII (FXII) is the zymogen of a plasma protease (FXIIa) that contributes to bradykinin generation by converting prekallikrein to the protease plasma kallikrein (PKa). FXII conversion to FXIIa by autocatalysis or PKa-mediated cleavage is enhanced when the protein binds to negatively charged "surfaces" such as polymeric orthophosphate. FXII is comprised of non-catalytic (heavy chain) and catalytic (light chain) regions. The heavy chain promotes FXII surface-binding and surface-dependent activation, but restricts activation when FXII is not surface-bound. From the N-terminus, the heavy chain contains fibronectin type II (FN2), epidermal growth factor-1 (EGF1), fibronectin type I (FN1), EGF2, and kringle (KNG) domains, and a proline-rich region (PRR). It shares this organization with its homolog, pro-hepatocyte growth factor activator (Pro-HGFA). To study the importance of heavy chain domains to FXII function, we prepared FXII with replacements of each domain with corresponding Pro-HGFA domains, and tested them in activation and activity assays. EGF1 is required for surface-dependent FXII autoactivation and surface-dependent prekallikrein activation by FXIIa. KNG and FN2 are important for limiting FXII activation in the absence of a surface by a process that may require interactions between a lysine/arginine binding site on KNG and basic residues elsewhere on FXII. This interaction is disrupted by the lysine analog Ɛ-aminocaproic acid. A model is proposed in which an Ɛ-aminocaproic acid-sensitive interaction between the KNG and FN2 domains maintains FXII in a conformation that restricts activation. Upon binding to a surface through EGF1, the KNG/FN2-dependent mechanism is inactivated, exposing the FXII activation cleavage site.

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Section: Discussionmentioning

confidence: 99%

Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains

et al. 2022

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“…Without close monitoring and control of bloodstream heparin levels, potentially fatal heparin overdose effects, such as internal hemorrhaging, can occur. 1 Various chemical sensors for heparin detection have been developed using appropriate signal transductions such as spectroscopy, 2 voltammetry, 3 quartz microbalance 4 and conductometry. 5 Potentiometric sensors are generic and highly successful approaches to chemical sensing, and polyion-selective membrane electrodes have shown to be very promising in biomedical analysis.…”

Section: Introductionmentioning

confidence: 99%

Polycation-sensitive membrane electrode for determination of heparin based on controlled release of protamine

Chen

Ding

Qin

2012

Analyst

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A polycation-selective polymeric membrane electrode using dinonylnaphthalene sulfonate as an ion exchanger has been developed as a protamine controlled-release system for potentiometric detection of heparin. The incorporation of tetradodecylammonium tetrakis(4-chlorophenyl)borate as a lipophilic salt in the membrane dramatically improves the sensor's selectivity towards protamine over sodium ions via influencing the activity coefficient of protamine in the membrane, and a stable potential baseline can be obtained in the presence of an electrolyte background. The electrostatic binding interaction between heparin and protamine decreases the concentration of free protamine released at the sample-membrane interface and facilitates the stripping of protamine out of the membrane surface via the ion-exchange process with sodium ions, thus decreasing the membrane potential. Under optimal conditions, the proposed polymeric membrane electrode exhibits a linear relationship between the initial slope of the potential change and the heparin concentration in the range of 0.025-1.25 U mL À1 with an improved detection limit of 0.01 U mL À1 .

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“…1 At the end of the reaction, fondaparinux is released without any conformational or chemical changes, and can be used again to bind to another antithrombin molecule. 2 This molecule does not bind to plasma proteins and therefore has a predictive pharmacological effect. Its half-life in plasma is 17 hours and is dose-independent.…”

Section: Pentasaccharidementioning

confidence: 99%

New trends in anticoagulant treatments

Pengo

2005

Lupus

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Classic anticoagulant drugs are very effective, save lives and have been used for more than 50 years. Nevertheless, some drawbacks are encountered in their routine clinical use. Recently, pharmaceutical research has developed new drugs, some of which are already on the market. This is the case of fondaparinux, a pentasaccharide which can interact with antithrombin, thus inhibiting factor Xa. Modification of its structure (idraparinux) has led to more stable binding with antithrombin and to an increase in its half-life allowing for once-a-week administration. Another important oral compound is ximelagatran which directly binds thrombin and blocks its catalytic site. There is no need for laboratory control, and phase II and phase III studies are encouraging. Thus, in the next few years, we may witness great changes in the treatment of patients with thromboembolic disorders.

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Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement.

Cited by 457 publications

References 48 publications

Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains

Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains

Polycation-sensitive membrane electrode for determination of heparin based on controlled release of protamine

New trends in anticoagulant treatments

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