1 research outputs found
Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases
Allylic cyclitols
were investigated as covalent inhibitors
of glycoside
hydrolases by chemical, enzymatic, proteomic, and computational methods.
This approach was inspired by the C7 cyclitol natural product
streptol glucoside, which features a potential carbohydrate leaving
group in the 4-position (carbohydrate numbering). To test this hypothesis,
carbocyclic inhibitors with leaving groups in the 4- and 6- positions
were prepared. The results of enzyme kinetics analyses demonstrated
that dinitrophenyl ethers covalently inhibit α-glucosidases
of the GH13 family without reactivation. The labeled enzyme was studied
by proteomics, and the active site residue Asp214 was identified as
modified. Additionally, computational studies, including enzyme homology
modeling and density functional theory (DFT) calculations, further
delineate the electronic and structural requirements for activity.
This study demonstrates that previously unexplored 4- and 6-positions
can be exploited for successful inhibitor design