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 th e reaction catalysed by the glutamine amide transfer domain of Candida albicans glucosamine 6-phosphate synthase have been designed and synt hesized. Esters and amides of gamma-phosphonic and gamma-sulfonic anal ogs of glutamine and glutamic acid were tested as potential inhibitors of the enzyme. N-substituted amides 9 and 15 were found to be the str ongest inhibitors in the series. Structure-activity relationship studi es led to conclusions supporting the possibility of a direct nucleophi lic 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. (C) 1997 Acade mic Press.