Investigation of Mechanism of Nitrogen Transfer in Glucosamine 6-Phosphate Synthase with the Use of Transition State Analogs

Several structural analogs of putative tetrahedral intermediates of the reaction catalyzed by the glutamine amide transfer domain ofCandida albicansglucosamine 6-phosphate synthase have been designed and synthesized. Esters and amides of γ-phosphonic and γ-sulfonic analogs of glutamine and glutamic acid were tested as potential inhibitors of the enzyme. N-substituted amides9and15were found to be the strongest inhibitors in the series. Structure–activity relationship studies led to conclusions supporting the possibility of a direct nucleophilic attack of the glutamine amide nitrogen on an electrophilic site of the enzyme-bound fructose 6-phosphate as the most likely mechanism of nitrogen transfer in glucosamine 6-phosphate synthase.