Role of isopeptidolysis in the process of thrombolysis

Baskova, I. P.; Kalabushev, S.; Akhaev, D.N.; Bobrovsky, Pavel A.; Manuvera, Valentin A.; Лазарев, В. Н.

doi:10.1016/j.thromres.2018.03.007

Cited by 4 publications

(4 citation statements)

References 16 publications

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“…In our previous study, we demonstrated the ability of recombinant destabilase to irreversibly lyse aged arterial thrombi in vivo in an experimental rat thrombosis model [35]. Here, we examined the mechanism of thrombolysis in vitro.…”

Section: Introductionmentioning

confidence: 95%

Recombinant Destabilase from Hirudo medicinalis Is Able to Dissolve Human Blood Clots In Vitro

Bobrovsky

Manuvera

Baskova

et al. 2021

CIMB

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Leeches are amazing animals that can be classified as conditionally poisonous animals since the salivary cocktail they produce is injected directly into the victim, and its components have strictly defined biological purposes, such as preventing blood clot formation. Thrombolytic drugs are mainly aimed at treating newly formed blood clots. Aged clots are stabilized by a large number of isopeptide bonds that prevent the action of thrombolytics. These bonds are destroyed by destabilase, an enzyme of the leech’s salivary glands. Here, we conducted a pilot study to evaluate the feasibility and effectiveness of the use of destabilase in relation to blood clots formed during real pathological processes. We evaluated the isopeptidase activity of destabilase during the formation of a stabilized fibrin clot. We showed that destabilase does not affect the internal and external coagulation cascades. We calculated the dose–response curve and tested the ability of destabilase to destroy isopeptide bonds in natural blood clots. The effect of aged and fresh clots dissolving ability after treatment with destabilase coincided with the morphological characteristics of clots during surgery. Thus, recombinant destabilase can be considered as a potential drug for the treatment of aged clots, which are difficult to treat with known thrombolytics.

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Section: Introductionmentioning

confidence: 95%

Recombinant Destabilase from Hirudo medicinalis Is Able to Dissolve Human Blood Clots In Vitro

Bobrovsky

Manuvera

Baskova

et al. 2021

CIMB

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“…Due to its isopeptidase activity destabilase dissolutes stabilized fibrin and cleaves the bond formed between side chains of lysine and glutamine residues in the D-dimer (the final product of fibrinolysis) 9 . Predictably, destabilase greatly increases the thrombolysis of both venous and arterial thrombi in rat model 4 and destroys old, preliminarily formed thrombi in in vitro and in vivo experiments 11 , 14 . This ability makes destabilase a promising thrombolytic drug candidate with reduced side effects and increased effectivity 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Predictably, destabilase greatly increases the thrombolysis of both venous and arterial thrombi in rat model 4 and destroys old, preliminarily formed thrombi in in vitro and in vivo experiments 11 , 14 . This ability makes destabilase a promising thrombolytic drug candidate with reduced side effects and increased effectivity 4 . Despite evident importance, the structure of destabilase remains unrevealed until now.…”

Section: Introductionmentioning

confidence: 99%

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Structural insights into thrombolytic activity of destabilase from medicinal leech

Marin

Kornilov

Bukhdruker

et al. 2023

Sci Rep

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Destabilase from the medical leech Hirudo medicinalis belongs to the family of i-type lysozymes. It has two different enzymatic activities: microbial cell walls destruction (muramidase activity), and dissolution of the stabilized fibrin (isopeptidase activity). Both activities are known to be inhibited by sodium chloride at near physiological concentrations, but the structural basis remains unknown. Here we present two crystal structures of destabilase, including a 1.1 Å-resolution structure in complex with sodium ion. Our structures reveal the location of sodium ion between Glu34/Asp46 residues, which were previously recognized as a glycosidase active site. While sodium coordination with these amino acids may explain inhibition of the muramidase activity, its influence on previously suggested Ser49/Lys58 isopeptidase activity dyad is unclear. We revise the Ser49/Lys58 hypothesis and compare sequences of i-type lysozymes with confirmed destabilase activity. We suggest that the general base for the isopeptidase activity is His112 rather than Lys58. pKa calculations of these amino acids, assessed through the 1 μs molecular dynamics simulation, confirm the hypothesis. Our findings highlight the ambiguity of destabilase catalytic residues identification and build foundations for further research of structure–activity relationship of isopeptidase activity as well as structure-based protein design for potential anticoagulant drug development.

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Protein-peptide based assay for the characterization of human blood coagulation factor XIII-A isopeptidase activity

Csobán-Szabó

Fésüs

Király

2020

Analytical Biochemistry

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Role of isopeptidolysis in the process of thrombolysis

Cited by 4 publications

References 16 publications

Recombinant Destabilase from Hirudo medicinalis Is Able to Dissolve Human Blood Clots In Vitro

Recombinant Destabilase from Hirudo medicinalis Is Able to Dissolve Human Blood Clots In Vitro

Structural insights into thrombolytic activity of destabilase from medicinal leech

Protein-peptide based assay for the characterization of human blood coagulation factor XIII-A isopeptidase activity

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