Sugary shapes in the spotlight (again)
As part of an ongoing interest in understanding enzymes that process the sugar mannose, attention in the Williams group has focussed on a family of glycosidases for which the catalytic details remain obscure: α-mannosidases of glycoside hydrolase family 125.
In collaboration with theoreticians from Spain and structural biologists from the UK, the catalytic mechanism of this intriguing and biomedically-important class of enzymes has been finally elucidated (Alonso-Gil, S., Males, A., Fernandes, P., Williams, S.J., Davies, G.J., Rovira, C., Computational design-of-experiment unveils the conformational reaction coordinate of GH125 α-mannosidases, J. Am. Chem. Soc., 2017, 139, 1085−1088).
A quantum mechanical, computational approach was used to predict the misleading nature of past structural work, and to design an experimental approach that allowed collection of X-ray crystallographic data that supported the computational prediction.
The work contributes a missing jigsaw piece to the complex stereoelectronic and conformational details of enzymatic mannose chemistry, and can be used as a blueprint for synthesis of selective inhibitors.
Professor Spencer J Williams