Glutamate Dehydrogenase 1 - Regulation

Regulation

When GLUD1 is highly saturated with the active site ligands (substrates), an inhibitory abortive complex forms in the active site: NAD(P)H.Glu in the oxidative deamination reaction at high pH, and NAD(P)+.2-oxoglutarate in the reductive amination reaction at low pH. GLUD1 assumes its basal state configuration in the absence of allosteric effectors, regardless of whether the allosteric sites are functional. The allosteric regulators of GLUD1 - ADP, GTP, Leu, NAD+ and NADH - exert their effects by changing the energy required to open and close the catalytic cleft during enzymic turnover, in other words by destabilizing or stabilizing, respectively, the abortive complexes. Activators are not necessary for the catalytic function of GLUD1, as it is active in the absence of these compounds (basal state). It has been suggested that GLUD1 assumes in its basal state a configuration (open catalytic cleft) that permits catalytic activity regardless of whether the allosteric sites are functional. GLUD regulation is of particular biological importance as exemplified by observations showing that regulatory mutations of GLUD1 are associated with clinical manifestations in children.