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, respectively, for the inhibition of gamma-glutamylcysteine synthetase and glutamine synthetase. The former served as a poor inhibitor of both enzymes, but the latter inhibited glutamine synthetase with a Ki of 59 microM and partially inactivated the enzyme in an NH3- and ATP-dependent manner.
Inoue
M
M
Institute for Chemical Research, Kyoto University, Japan.
Hiratake
J
J
Sakata
K
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004926:Escherichia coli / Q000201:enzymology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008956:Models, Chemical
D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D005974:Glutamate-Ammonia Ligase; D005721:Glutamate-Cysteine Ligase