Structural insights into thrombolytic activity of destabilase from medicinal leech
Research article published in Scientific reports (2023)
Abstract
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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
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).
Why This Matters for Hirudotherapy
This study determined high-resolution crystal structures of destabilase, an enzyme from the medicinal leech Hirudo medicinalis with both muramidase and fibrin-dissolving isopeptidase activities, to investigate the structural basis of sodium ion inhibition and to clarify which catalytic residues drive isopeptidase function. Because destabilase's isopeptidase activity can dissolve stabilized fibrin, understanding its structure and catalytic mechanism contributes to the molecular-level characterization of a leech-derived enzyme with fibrinolytic properties. The work is confined to protein crystallography and computational molecular dynamics simulation; it does not examine hirudotherapy, clinical outcomes, or therapeutic application of any kind. The abstract states only that these structural foundations may inform future anticoagulant drug design, which the study itself does not test or validate.
Citation
Structural insights into thrombolytic activity of destabilase from medicinal leech.
Marin E et al. · Scientific reports, 2023
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