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A Native Ternary Complex Trapped in a Crystal Reveals the Catalytic Mechanism of a Retaining Glycosyltransferase

DOI: 10.1002/ange.201504617 DOI Help

Authors: David Albesa-jove (Universidad del País Vasco) , Fernanda Mendoza (Institut de Biotecnologia i de Biomedicina) , Ane Rodrigo-unzueta (Universidad del País Vasco) , Fernando Gomollón-bel (Universidad de Zaragoza) , Javier O. Cifuente (Universidad del País Vasco) , Saioa Urresti (Universidad del País Vasco) , Natalia Comino (Universidad del País Vasco) , Hansel Gómez (IRB Barcelona) , Javier Romero-garcía (Universitat Ramon Llull) , José M. Lluch (Universitat Autònoma de Barcelona) , Enea Sancho-vaello (Universidad del País Vasco) , Xevi Biarnés (Universitat Ramon Llull) , Antoni Planas (Universitat Ramon Llull) , Pedro Merino (Universidad de Zaragoza) , Laura Masgrau (Institut de Biotecnologia i de Biomedicina) , Marcelo E. Guerin (Universidad del País Vasco)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie , VOL 127 , PAGES 10036 - 10040

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 8302 , 10130

Abstract: Glycosyltransferases (GTs) comprise a prominent family of enzymes that play critical roles in a variety of cellular processes, including cell signaling, cell development, and host–pathogen interactions. Glycosyl transfer can proceed with either inversion or retention of the anomeric configuration with respect to the reaction substrates and products. The elucidation of the catalytic mechanism of retaining GTs remains a major challenge. A native ternary complex of a GT in a productive mode for catalysis is reported, that of the retaining glucosyl-3-phosphoglycerate synthase GpgS from M. tuberculosis in the presence of the sugar donor UDP-Glc, the acceptor substrate phosphoglycerate, and the divalent cation cofactor. Through a combination of structural, chemical, enzymatic, molecular dynamics, and quantum-mechanics/molecular-mechanics (QM/MM) calculations, the catalytic mechanism was unraveled, thereby providing a strong experimental support for a front–side substrate-assisted SNi-type reaction.

Journal Keywords: Enzyme; Enzymkatalyse; Glykosyltransferasen; Reaktionsmechanismen; Strukturaufklärung

Subject Areas: Chemistry


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: Soleil