Allosteric Regulation of Glutamate Dehydrogenase

Abstract

Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate to α-ketoglutarate and, in animals, is allosterically regulated by a wide array of metabolites. The role of this complex allosteric regulation was made evident by hyperinsulinism/hyperammonemia syndrome (HHS). In HHS, mutations desensitize GDH to allosteric inhibition by GTP leading to excessive insulin secretion, increase in plasma ammonium levels, and dysregulation of glutamate levels in the brain leading to seizures and developmental delays. The current treatment for HHS is the potassium channel activator, diazoxide, which only addresses the hyperinsulinism aspect of the disease. Only by targeting GDH directly can all of the multi-organ symptoms of HHS be addressed. We have just screened more than 250,000 compounds for both activators and inhibitors of GDH. These compounds will not only have direct clinical applications for treating HHS but will elucidate the atomic details of GDH regulation. In the case of the latter, we have also deleted the unusual 50-residue ‘antenna’ feature of the enzyme and are finding that it plays a fundamental role in catalytic turnover in rather unexpected ways.