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Porciúncula-González C, Cagnoni AJ, Fontana C, et al. Structural insights in galectin-1-glycan recognition: Relevance of the glycosidic linkage and the N-acetylation pattern of sugar moieties. Bioorg Med Chem. 2021;44:116309doi: 10.1016/j.bmc.2021.116309.
Porciúncula-González, C., Cagnoni, A. J., Fontana, C., Mariño, K. V., Saenz-Méndez, P., Giacomini, C., & Irazoqui, G. (2021). Structural insights in galectin-1-glycan recognition: Relevance of the glycosidic linkage and the N-acetylation pattern of sugar moieties. Bioorganic & medicinal chemistry, 44116309. https://doi.org/10.1016/j.bmc.2021.116309
Porciúncula-González, Cecilia, et al. "Structural insights in galectin-1-glycan recognition: Relevance of the glycosidic linkage and the N-acetylation pattern of sugar moieties." Bioorganic & medicinal chemistry vol. 44 (2021): 116309. doi: https://doi.org/10.1016/j.bmc.2021.116309
Porciúncula-González C, Cagnoni AJ, Fontana C, Mariño KV, Saenz-Méndez P, Giacomini C, Irazoqui G. Structural insights in galectin-1-glycan recognition: Relevance of the glycosidic linkage and the N-acetylation pattern of sugar moieties. Bioorg Med Chem. 2021 Aug 15;44:116309. doi: 10.1016/j.bmc.2021.116309. Epub 2021 Jul 14. PMID: 34293617.
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Bioorg Med Chem. 2021 Aug 15;44:116309. doi: 10.1016/j.bmc.2021.116309. Epub 2021 Jul 14.

Structural insights in galectin-1-glycan recognition: Relevance of the glycosidic linkage and the N-acetylation pattern of sugar moieties.

Bioorganic & medicinal chemistry

Cecilia Porciúncula-González, Alejandro J Cagnoni, Carolina Fontana, Karina V Mariño, Patricia Saenz-Méndez, Cecilia Giacomini, Gabriela Irazoqui

Affiliations

  1. Laboratorio de Bioquímica, Departamento de Biociencias, Facultad de Química, UdelaR, Gral. Flores, 2124, 11800 Montevideo, Uruguay; Computational Chemistry and Biology Group, DETEMA, Facultad de Química, UdelaR, Isidoro de María 1614, 11800 Montevideo, Uruguay; Graduate Program in Chemistry, Facultad de Química, Universidad de la República, Uruguay.
  2. Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1428ADN Buenos Aires, Argentina.
  3. Laboratorio de Espectroscopía y Fisicoquímica Orgánica, Departamento de Química del Litoral, CENUR Litoral Norte (S.R.A. Facultad de Química), UdelaR, Ruta 3 km 363, 60000 Paysandú, Uruguay.
  4. Computational Chemistry and Biology Group, DETEMA, Facultad de Química, UdelaR, Isidoro de María 1614, 11800 Montevideo, Uruguay; Department of Engineering and Chemical Sciences, Faculty of Health, Science and Technology, Karlstad University, Universitetsgatan 2, 651 88 Karlstad, Sweden.
  5. Laboratorio de Bioquímica, Departamento de Biociencias, Facultad de Química, UdelaR, Gral. Flores, 2124, 11800 Montevideo, Uruguay.
  6. Laboratorio de Bioquímica, Departamento de Biociencias, Facultad de Química, UdelaR, Gral. Flores, 2124, 11800 Montevideo, Uruguay. Electronic address: [email protected].

PMID: 34293617 DOI: 10.1016/j.bmc.2021.116309

Abstract

Galectins, soluble lectins widely expressed intra- and extracellularly in different cell types, play major roles in deciphering the cellular glycocode. Galectin-1 (Gal-1), a prototype member of this family, presents a carbohydrate recognition domain (CRD) with specific affinity for β-galactosides such as N-acetyllactosamine (β-d-Galp-(1 → 4)-d-GlcpNAc), and mediate numerous physiological and pathological processes. In this work, Gal-1 binding affinity for β-(1 → 6) galactosides, including β-d-Galp-(1 → 6)-β-d-GlcpNAc-(1 → 4)-d-GlcpNAc was evaluated, and their performance was compared to that of β-(1 → 4) and β-(1 → 3) galactosides. To this end, the trisaccharide β-d-Galp-(1 → 6)-β-d-GlcpNAc-(1 → 4)-d-GlcpNAc was enzymatically synthesized, purified and structurally characterized. To evaluate the affinity of Gal-1 for the galactosides, competitive solid phase assays (SPA) and isothermal titration calorimetry (ITC) studies were carried out. The experimental dissociation constants and binding energies obtained were compared to those calculated by molecular docking. These analyses evidenced the critical role of the glycosidic linkage between the terminal galactopyranoside residue and the adjacent monosaccharide, as galactosides bearing β-(1 → 6) glycosidic linkages showed dissociation constants six- and seven-fold higher than those involving β-(1 → 4) and β-(1 → 3) linkages, respectively. Moreover, docking experiments revealed the presence of hydrogen bond interactions between the N-acetyl group of the glucosaminopyranose moiety of the evaluated galactosides and specific amino acid residues of Gal-1, relevant for galectin-glycan affinity. Noticeably, the binding free energies (ΔG

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: Disaccharides; Enzymatic synthesis; Galectin inhibitors; Galectin ligand interactions; Galectin-1; Glycosidic linkage; Molecular modelling; Trisaccharide

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