Covalent Heparin Cofactor II-Heparin and Heparin Cofactor II-Dermatan Sulfate Complexes

Monagle, Paul; Berry, Leslie R.; O’Brodovich, Hugh; Andrew, Maureen; Chan, Anthony

doi:10.1074/jbc.273.50.33566

Cited by 11 publications

(6 citation statements)

References 39 publications

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“…In addition, because fibrin binds exosite I on thrombin, fibrinbound thrombin is more resistant to inhibition by HCII than by AT (32). Therefore, it has been reported that covalent conjugation of HCII and dermatan sulfate may be superior for the inhibition of clot-associated coagulant activity (33). Since the inhibition of thrombin by HCII activated with Ca-SP does not require the N-terminal acidic domain, Ca-SP-activated HCII may play an important role in the inhibition of fibrin-bound thrombin.…”

Section: Discussionmentioning

confidence: 99%

Activation of Heparin Cofactor II by Calcium Spirulan

Hayakawa¹,

Hayashi²,

Lee³

et al. 2000

Journal of Biological Chemistry

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Heparin cofactor II (HCII) is a plasma serine protease inhibitor whose ability to inhibit ␣-thrombin is accelerated by a variety of sulfated polysaccharides in addition to heparin and dermatan sulfate. Previous investigations have indicated that calcium spirulan (Ca-SP), a novel sulfated polysaccharide, enhanced the rate of inhibition of ␣-thrombin by HCII. In this study, we investigated the mechanism of the activation of HCII by Ca-SP. Interestingly, in the presence of Ca-SP, an N-terminal deletion mutant of HCII (rHCII-⌬74) inhibited ␣-thrombin, as native recombinant HCII (native rH-CII) did. The second-order rate constant for the inhibition of ␣-thrombin by rHCII-⌬74 was 2.0 ؋ 10 8 M ؊1 min ؊1 in the presence of 50 g/ml Ca-SP and 10,000-fold higher than in the absence of Ca-SP. The rates of native rHCII and rHCII-⌬74 for the inhibition of ␥-thrombin were increased only 80-and 120-fold, respectively. Our results suggested that the anion-binding exosite I of ␣-thrombin was essential for the rapid inhibition reaction by HCII in the presence of Ca-SP and that the N-terminal acidic domain of HCII was not required. Therefore, we proposed a mechanism by which HCII was activated allosterically by Ca-SP and could interact with the anionbinding exosite I of thrombin not through the N-terminal acidic domain of HCII. The Arg 103 3 Leu mutant bound to Ca-SP-Toyopearl with normal affinity and inhibited ␣-thrombin in a manner similar to native rHCII. These results indicate that Arg 103 in HCII molecule is not critical for the interaction with Ca-SP.Thrombin is considered to be the pivotal enzyme in the coagulation pathway (1). Besides its critical role in hemostasis, thrombin elicits cellular responses through the thrombin receptor that may contribute to inflammation, wound healing, and atherosclerosis (2). Heparin cofactor II (HCII) 1 is an important plasma protein that selectively inhibits thrombin (3). A number of sulfated polysaccharides in addition to heparin and dermatan sulfate catalyze HCII to accelerate markedly the reaction of HCII with thrombin (4 -6). Marine algae are a rich source of sulfated polysaccharides with novel structures (7).Calcium spirulan (Ca-SP) is a novel sulfated polysaccharide isolated from a blue-green alga Spirulina platensis by Hayashi et al. (8,9). They reported an inhibitory effect of Ca-SP on the replication of enveloped viruses. We have recently showed that Ca-SP enhances the rate of inhibition of thrombin by HCII and that the molecular conformation maintained by calcium ions is essential to exhibit antithrombin activity (10). However, the mechanism of activation of HCII by Ca-SP has not been clarified. Current evidence suggests that binding of either heparin or dermatan sulfate to HCII displaces the N-terminal acidic domain of the inhibitor, which normally occupies the glycosaminoglycan-binding site. The N-terminal acidic domain then binds to the anion-binding exosite I of thrombin, facilitating proteolytic attack on the reactive site peptide bond of HCII (11). Deletions within the N-te...

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Section: Discussionmentioning

confidence: 99%

Activation of Heparin Cofactor II by Calcium Spirulan

Hayakawa¹,

Hayashi²,

Lee³

et al. 2000

Journal of Biological Chemistry

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“…119 Recently, covalent complexes of DS and heparin with heparin cofactor II have been prepared and shown to be good inhibitors of thrombin. 120 These covalent complexes were prepared in a manner similar to covalent heparin-antithrombin complexes. 112 The heparin cofactor II-DS complex has fast bimolecular rate constants approaching diffusion limits ($10 7 M À1 sec À1 ) for reactions with thrombin.…”

Section: Other Carbohydrate-based Polymersmentioning

confidence: 99%

New antithrombin‐based anticoagulants

Desai

2003

Medicinal Research Reviews

131

115

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Clinically used anticoagulants are inhibitors of enzymes involved in the coagulation pathway, primarily thrombin and factor Xa. These agents can be either direct or indirect inhibitors of clotting enzymes. Heparin-based anticoagulants are indirect inhibitors that enhance the proteinase inhibitory activity of a natural anticoagulant, antithrombin. Despite its phenomenal success, current anticoagulation therapy suffers from the risk of serious bleeding. The need for safer and more effective antithrombotic agents clearly exists. The past decade has seen enormous effort directed toward discovering and/or designing new molecules with anticoagulant activity. These new molecules can be classified into (a). antithrombin and its mutants, (b). natural polysaccharides, (c). synthetic modified heparins and heparin-mimics, (d). synthetic oligosaccharides, and (e). synthetic non-sugar antithrombin activators. This review focuses on these efforts in designing or discovering new molecules that act through the antithrombin pathway of anticoagulation.

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“…SERPINC1 can inhibit factor Xa and thrombin as a potent inhibitor of blood coagulation [41]. SERPIND1 is a plasma glycoprotein that inhibit thrombin specifically, which is activated by heparin or dermatan sulfate [42,43]. ANXA5 is a member of the annexin proteins as anticoagulant and antithrombotic protein [44].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of tanshinones and phenolic acids from Danshen in the treatment of coronary heart disease based on co-expression network

Huo

Chen

et al. 2020

BMC Complement Med Ther

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Background: The tanshinones and phenolic acids in Salvia miltiorrhiza (also named Danshen) have been confirmed for the treatment of coronary heart disease (CHD), but the action mechanisms remain elusive. Methods: In the current study, the co-expression protein interaction network (Ce-PIN) was used to illustrate the differences between the tanshinones and phenolic acids of Danshen in the treatment of CHD. By integrating the gene expression profile data and protein-protein interactions (PPIs) data, the Ce-PINs of tanshinones and phenolic acids were constructed. Then, the Ce-PINs were analyzed by gene ontology enrichment analyzed based on the optimal algorithm. Results: It turned out that Danshen is able to treat CHD by regulating the blood circulation, immune response and lipid metabolism. However, phenolic acids may regulate the blood circulation by Extracellular calcium-sensing receptor (CaSR), Endothelin-1 receptor (EDNRA), Endothelin-1 receptor (EDNRB), Kininogen-1 (KNG1), tanshinones may regulate the blood circulation by Guanylate cyclase soluble subunit alpha-1 (GUCY1A3) and Guanylate cyclase soluble subunit beta-1 (GUCY1B3). In addition, both the phenolic acids and tanshinones may regulate the immune response or inflammation by T-cell surface glycoprotein CD4 (CD4), Receptor-type tyrosine-protein phosphatase C (PTPRC). Conclusion: Through the same targets of the same biological process and different targets of the same biological process, the tanshinones and phenolic acids synergistically treat coronary heart disease.

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Covalent Heparin Cofactor II-Heparin and Heparin Cofactor II-Dermatan Sulfate Complexes

Cited by 11 publications

References 39 publications

Activation of Heparin Cofactor II by Calcium Spirulan

Activation of Heparin Cofactor II by Calcium Spirulan

New antithrombin‐based anticoagulants

Mechanism of tanshinones and phenolic acids from Danshen in the treatment of coronary heart disease based on co-expression network

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