The Essential Role of Water Molecules in the Reaction Mechanism of Protein O-Fucosyltransferase 2.

Autor: Sanz-Martínez I; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)., Universidad de Zaragoza, 50018, Zaragoza, Spain., García-García A; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)., Universidad de Zaragoza, 50018, Zaragoza, Spain., Tejero T; Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)., Universidad de Zaragoza-CSIC, 50009, Zaragoza, Spain., Hurtado-Guerrero R; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)., Universidad de Zaragoza, 50018, Zaragoza, Spain.; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark.; Fundación ARAID, Zaragoza, 50018, Spain., Merino P; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)., Universidad de Zaragoza, 50018, Zaragoza, Spain.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2022 Nov 25; Vol. 61 (48), pp. e202213610. Date of Electronic Publication: 2022 Nov 10.
DOI: 10.1002/anie.202213610
Abstrakt: Protein O-fucosyltransferase 2 (PoFUT2) is an inverting glycosyltransferase (GT) that fucosylates thrombospondin repeats (TSRs) from group 1 and 2. PoFUT2 recognizes a large and diverse number of TSRs through a dynamic network of water-mediated interactions. By X-ray structural studies of C. elegans PoFUT2 complexed to a TSR of group 2, we demonstrate that this GT recognizes similarly the 3D structure of TSRs from both groups 1 and 2. Its active site is highly exposed to the solvent, suggesting that water molecules might also play an essential role in the fucosylation mechanism. We applied QM/MM methods using human PoFUT2 as a model, and found that HsPoFUT2 follows a classical S N 2 reaction mechanism in which water molecules contribute to a great extent in facilitating the release of the leaving pyrophosphate unit, causing the H transfer from the acceptor nucleophile (Thr/Ser) to the catalytic base, which is the last event in the reaction. This demonstrates the importance of water molecules not only in recognition of the ligands but also in catalysis.
(© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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