Synthesis and characterization of intermediate and transition-state analogue inhibitors of gamma-glutamyl peptide ligases

The phosphonodifluoromethyl ketone and phosphonofluoridate derivatives of L -glutamic acid were synthesized and characterized as analogues of the gamma -glutamyl phosphate intermediate and the tetrahedral transition state, resp ectively, for the inhibition of gamma-glutamylcysteine synthetase and gluta mine synthetase. The former served as a poor inhibitor of both enzymes, but the latter inhibited glutamine synthetase wifh a K-i of 59 mu M and partia lly inactivated the enzyme in an NH3- and ATP-dependent manner.