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Glycomimetics Targeting Glycosyltransferases: Synthetic, Computational and Structural Studies of Less-Polar Conjugates

DOI: 10.1002/chem.201600467 DOI Help

Authors: Mattia Ghirardello (Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza) , Matilde De Las Rivas (University of Zaragoza) , Alessandra Lacetera (Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, CIB-CSIC) , Ignacio Delso (Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza) , Erandi Lira-navarette (University of Zaragoza) , Tomás Tejero (Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza) , Sonsoles Martín-santamaría (Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, CIB-CSIC) , Ramon Hurtado-guerrero (University of Zaragoza) , Pedro Merino (Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry - A European Journal , VOL 22 , PAGES 7215 - 7224

State: Published (Approved)
Published: May 2016
Diamond Proposal Number(s): 10121

Abstract: The Leloir donors are nucleotide sugars essential for a variety of glycosyltransferases (GTs) involved in the transfer of a carbohydrate to an acceptor substrate, typically a protein or an oligosaccharide. A series of less-polar nucleotide sugar analogues derived from uridine have been prepared by replacing one phosphate unit with an alkyl chain. The methodology is based on the radical hydrophosphonylation of alkenes, which allows coupling of allyl glycosyl compounds with a phosphate unit suitable for conjugation to uridine. Two of these compounds, the GalNAc and galactose derivatives, were further tested on a model GT, such as GalNAc-T2 (an important GT widely distributed in human tissues), to probe that both compounds bound in the medium-high micromolar range. The crystal structure of GalNAc-T2 with the galactose derivative traps the enzyme in an inactive form; this suggests that compounds only containing the β-phosphate could be efficient ligands for the enzyme. Computational studies with GalNAc-T2 corroborate these findings and provide further insights into the mechanism of the catalytic cycle of this family of enzymes.

Journal Keywords: carbohydrates; glycomimetics; glycosyltransferases; molecular modeling; proteins

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography