Synthesis and Testing of Sugar Phosphofluoridates and Cyclic Phosphates as Inhibitors of Phosphoglucomutase

Article abstract of DOI:10.1021/jo00029a007

Three aldose phosphofluoridates, D-glucose 6-phosphofluoridate, α-D-mannopyranosyl phosphofluoridate, and 2-deoxy-2-fluoro-α-D-glucopyranosyl phosphofluoridate, have been synthesized from the parent phosphate and 2,4-dinitrofluorobenzene, and the mechanism of fluorination has been investigated.Another modified aldose phosphate, α-D-glucopyranosyl 4,6-cyclic phosphate has also been synthesized as an analogue of 6-phospho-α-D-glucopyranosyl phosphate.These compounds were tested as possible mechanism-based inactivators of rabbit muscle phosphoglucomutase, but no time-dependent inactivation was observed.They were, however, found to be reversible inhibitors of phosphoglucomutase, and comparison of their dissociation constants with those of parent phosphates revealed that the removal of a single negative charge weakens ground-state binding by approximately 11kJ/mol.Further, the absence of any detectable phosphorylation of these analogues reveals that this second charge is even more important for transition-state interactions, contributing at least 40kJ/mol to transition state stability.This suggests that the parent substrates bind to the enzyme and react in their dianionic forms, and it provides a measure of the value of charge-charge interactions at the active site of this key metabolic enzyme.