Synthesis and Characterization of Intermediate and Transition-State Analogue Inhibitors of γ-Glutamyl Peptide Ligases

Abstract

  The phosphonodifluoromethyl ketone and phosphonofluoridate derivatives of L-glutamic acid were synthesized and characterized as analogues of the γ-glutamyl phosphate intermediate and the tetrahedral transition state, respectively, for the inhibition of γ-glutamylcysteine synthetase and glutamine synthetase. The former served as a poor inhibitor of both enzymes, but the latter inhibited glutamine synthetase with a K_i of 59 μM and partially inactivated the enzyme in an NH₃- and ATP-dependent manner.