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

Von Wiley-VCH zur Verfügung gestellt

PoFUT2 is an inverting glycosyltransferase that fucosylates TSR repeats of group 1 and 2. By applying computational methodologies, it has been found that PoFUT2 follows a pure SN2 mechanism in which water molecules play an essential role in the catalysis. Recognition of the TSR repeats by direct and water-mediated interactions, together with the role of water molecules around the catalytic center, constitute the driving force of the process.


Abstract

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 SN2 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.

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