Rational Design of Glycomimetic Compounds Targeting the Saccharomyces cerevisiae Transglycosylase Gas2.
The transglycosylase Saccharomyces cerevisiae Gas2 (ScGas2) belongs to a large family of enzymes that are key players in yeast cell wall remodeling. Despite its biologic importance, no studies on the synthesis of substrate-based compounds as potential inhibitors have been reported. We have synthesized a series of docking-guided glycomimetics that were evaluated by fluorescence spectroscopy and saturation-transfer difference (STD) NMR experiments, revealing that a minimum of three glucose units linked via a β-(1,3) linkage are required for achieving molecular recognition at the binding donor site. The binding mode of our compounds is further supported by STD-NMR experiments using the active site-mutants Y107Q and Y244Q. Our results are important for both understanding of ScGas2-substrate interactions and setting up the basis for future design of glycomimetics as new antifungal agents.
Laboratorio de Síntesis Asimétrica, Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.|Servicio de Resonancia Magnética Nuclear, Centro de Química y Materiales de Aragón (CEQMA), CSIC, Universidad de Zaragoza, Campus San Francisco, Zaragoza, Aragón, 50009, Spain.
Ignacio
I
Delso
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), BIFI-IQFR (CSIC) Joint Unit, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.
Jessika
J
Valero-González
Laboratorio de Síntesis Asimétrica, Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.
Eduardo
E
Marca
Laboratorio de Síntesis Asimétrica, Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.
Tomás
T
Tejero
Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), BIFI-IQFR (CSIC) Joint Unit, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.|Fundación ARAID, Gobierno de Aragón, Zaragoza, Aragón 50009, Spain.
Ramón
R
Hurtado-Guerrero
Laboratorio de Síntesis Asimétrica, Departamento de Síntesis y Estructura de Biomoléculas, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC, Universidad de Zaragoza, Zaragoza, Aragón, 50009, Spain.
Pedro
P
Merino
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D005947:Glucose / Q000737:chemistry*; D006026:Glycoside Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014166:Transferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000935:Antifungal Agents; D009097:Multienzyme Complexes; D029701:Saccharomyces cerevisiae Proteins; C023176:transglycosidase enzyme system; D014166:Transferases; D006026:Glycoside Hydrolases; D005947:Glucose
STD-NMR; carbohydrates; docking; glycomimetics; transglycosylases