Inhibition of L-asparagine synthetase by mucochloric and mucobromic acids

Mucochloric and mucobromic acids are powerful inhibitors of tumoral and pancreatic L-asparagine synthetases. Two nitrogen donors, L-glutamine and ammonia, can be used by these enzymes; at a concentration of 1 mmol/l, mucochloric and mucobromic acids preferentially inhibit the utilization of ammonia as opposed to L-glutamine in vitro. Using the tumoral enzyme, kinetic analysis revealed that mucochloric acid produced inhibition which was apparently noncompetitive with ammonia but competitive with L-glutamine. In molar excess, L-glutamine and dithiothreitol effectively antagonized such inhibition; dialysis, however, failed to reverse established inhibition. These findings, suggest that the drugs operate by covalent attachment to crucial sulfhydryl functions on the enzyme.