ABSTRACT: Glutamate dehydrogenase (GDH) catalyzes the
oxidative deamination of L-glutamate and in animals is highly
regulated. GDH in hyperinsulinism/hyperammonemia syndrome
patients lacks GTP inhibition, resulting in hypersecretion of
insulin upon protein consumption. This suggests insulin secretion
could be stimulated with GDH activators. A high-throughput
screen yielded one potent activator, N1-[4-(2-aminopyrimidin-4-
yl)phenyl]-3-(trifluoromethyl)benzene-1-sulfonamide (75-E10).
75-E10 is ∼1000-fold more efficacious than the synthetic
activator, BCH, and is at least as effective as ADP. 75-E10 compound is highly effective at alleviating GTP inhibition and
may be binding to the ADP site. Unlike ADP, 75-E10 is activated over a broad range of conditions.