title: Glycomimetics Targeting Glycosyltransferases: Synthetic, Computational and Structural Studies of Less-Polar Conjugates.
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.
authors.affiliation: Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009, Zaragoza, Aragón, Spain.
authors.forename: Mattia
authors.initials: M
authors.lastname: Ghirardello
authors.affiliation: Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), BIFI-IQFR (CSIC) Joint Unit, Universidad de Zaragoza, 50009, Zaragoza, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: de Las Rivas
authors.affiliation: Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, CIB-CSIC, Ramiro de Maeztu, 9, 28040, Madrid, Spain.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lacetera
authors.affiliation: Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009, Zaragoza, Aragón, Spain.|Servicio de Resonancia Magnética Nuclear, Centro de Química y Materiales de Aragón (CEQMA), Universidad de Zaragoza, CSIC, Campus San Francisco, 50009, Zaragoza, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Delso
authors.affiliation: Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009, Zaragoza, Aragón, Spain.
authors.forename: Erandi
authors.initials: E
authors.lastname: Lira-Navarrete
authors.affiliation: Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009, Zaragoza, Aragón, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Tejero
authors.affiliation: Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, CIB-CSIC, Ramiro de Maeztu, 9, 28040, Madrid, Spain. smsantamaria@cib.csic.es.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
authors.affiliation: Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), BIFI-IQFR (CSIC) Joint Unit, Universidad de Zaragoza, 50009, Zaragoza, Spain. rhurtado@bifi.es.|Fundación ARAID, 50018, Zaragoza, Spain. rhurtado@bifi.es.|Instituto de Investigaciones Sanitarias de Aragón (IIS-A), Zaragoza, 50009, Spain. rhurtado@bifi.es.
authors.forename: Ramón
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.affiliation: Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009, Zaragoza, Aragón, Spain. pmerino@unizar.es.
authors.forename: Pedro
authors.identifier: 0000-0002-2202-3460
authors.initials: P
authors.lastname: Merino
mesh_terms: D000478:Alkylation; D020134:Catalytic Domain; D005690:Galactose / Q000031:analogs & derivatives / Q000378:metabolism; D006001:Glycoconjugates / Q000737:chemistry* / Q000378:metabolism*; D016695:Glycosyltransferases / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D017350:N-Acetylgalactosaminyltransferases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013379:Substrate Specificity; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D005690:Galactose; D006001:Glycoconjugates; D016695:Glycosyltransferases; D017350:N-Acetylgalactosaminyltransferases; D014529:Uridine; D000097763:Polypeptide N-acetylgalactosaminyltransferase
keywords: carbohydrates; glycomimetics; glycosyltransferases; molecular modeling; proteins