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.
Resumen
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).
Por qué esto importa para la hirudoterapia
Este estudio determinó las estructuras cristalinas de alta resolución de la destabilase, una enzima de la sanguijuela medicinal Hirudo medicinalis que posee tanto actividad muramidasa como actividad isopeptidasa capaz de disolver fibrina, con el fin de investigar la base estructural de la inhibición por iones de sodio y de esclarecer qué residuos catalíticos impulsan la función isopeptidasa. Debido a que la actividad isopeptidasa de la destabilase puede disolver la fibrina estabilizada, comprender su estructura y su mecanismo catalítico contribuye a la caracterización a nivel molecular de una enzima derivada de la sanguijuela con propiedades fibrinolíticas. El trabajo se circunscribe a la cristalografía de proteínas y a la simulación computacional de dinámica molecular; no examina la hirudoterapia, los resultados clínicos ni ninguna aplicación terapéutica de ningún tipo. El resumen únicamente afirma que estas bases estructurales podrían orientar el futuro diseño de fármacos anticoagulantes, lo cual el propio estudio no pone a prueba ni valida.
Citación
Structural insights into thrombolytic activity of destabilase from medicinal leech.
Marin E et al. · Scientific reports, 2023
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Añadido a la biblioteca ASH: March 18, 2026 · Última actualización del sitio: June 18, 2026