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Theoretical Grounding and Formation of Experimental Approaches to Hyaluronidase Structure Consolidation Due to Its Computational Interactions with Shortchain Glycosaminoglycan Ligands

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Abstract—

The computational study of a 3D model of the hyaluronidase interaction with shortchain glycosaminoglycan ligands demonstrated the diversity and significance of their reaction on enzyme structure. Exploratory computational consideration of the interaction of a 3D model of bovine testicular hyaluronidase (BTH) with short chain glycosaminoglycan ligands demonstrated the diversity and significance of their effect on the structure of the enzyme. The reported impact was due to electrostatic noncovalent interactions (without specific binding to the active site), causing noticeable conformational changes in the molecule biocatalyst/enzyme. As a result of this, the inactivation and stabilization of the enzyme globule are observed, and a change in its inhibition by heparin. The binding of chondroitin trimers (on centers cs2, cs4, cs7, cs8 or cs1, cs2, cs4, cs7, cs8) decreased the inhibition of the enzyme by tetramer heparin. The importance of ligand binding for the regulation of the functioning of the enzyme and the presence of a diverse and multicomponent microenvironment of the biocatalyst is noted. The sequence of preferential coupling of ligands with hyaluronidase is elicited in our study making it possible to evaluate the feasibility of achieving experimental selective modification of the enzyme (possibly noncovalently or covalently, for instance, with chondroitin sulfate trimers on centers cs7, cs1, cs5) for potential experimental production of stabilized forms of the enzyme. Promising approaches are noncovalent effects on hyaluronidase of chondroitin or chondroitin sulfate trimers, as well as covalent modification of the biocatalyst with chondroitin sulfate trimer or the production of genetically engineered derivatives of the enzyme. The mentioned changes in the structure of hyaluronidase may contribute to the implementation of its directed experimental design for subsequent biomedical research and practical clinical trials.

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Funding

The study was carried out with the financial support of the Ministry of Health of the Russian Federation (government task of the Academician E.I. Chazov, theme 121031300189-3).

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  1. Chazov National Medical Research Center of Cardiology, 121552, Moscow, Russia

    A. V. Maksimenko & R. Sh. Beabealashvili

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  1. A. V. Maksimenko
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  2. R. Sh. Beabealashvili
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Correspondence to A. V. Maksimenko.

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The authors declare no conflicts of interest.

The presented material does not contain a description of studies conducted by any of the authors of this work, involving people and using animals as research objects.

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Abbreviations: BTH, bovine testicular hyaluronidase; GAG, glycosaminoglycan; GN, hyaluronan; HP, heparin; CN, chondroitin; CS, chondroitin sulfate; β1AR, adrenergic receptor β1; 3D, spatial (tertiary) structure of the enzyme.

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Maksimenko, A.V., Beabealashvili, R.S. Theoretical Grounding and Formation of Experimental Approaches to Hyaluronidase Structure Consolidation Due to Its Computational Interactions with Shortchain Glycosaminoglycan Ligands. Russ J Bioorg Chem 49, 249–261 (2023). https://doi.org/10.1134/S1068162023020164

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