Regulation of human glutamate dehydrogenases: Implications for glutamate, ammonia and energy metabolism in brain

Abstract

Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate using NAD or NADP as cofactors. In mammalian brain, GDH is located predominantly in astrocytes, where it is probably involved in the metabolism of transmitter glutamate. The exact mechanisms that regulate glutamate fluxes through this pathway, however, have not been fully understood. In the human, GDH exists in heat-resistant and heat-labile isoforms, encoded by the GLUD1 (housekeeping) and GLUD2 (nerve tissue-specific) genes, respectively. These forms differ in their catalytic and allosteric properties. Kinetic studies showed that the K(m) value for glutamate for the nerve tissue GDH is within the range of glutamate levels in astrocytes (2.43 mM), whereas for the housekeeping enzyme, this value is significantly higher (7.64 mM; P < 0.01). The allosteric activators ADP (0.1-1.0 mM) and L-leucine (1.0-10.0 mM) induce a concentration-dependent enzyme stimulation that is proportionally greater for the nerve tissue-specific GDH (up to 1,600%) than for the housekeeping enzyme (up to 150%). When used together at lower concentrations, ADP (10-50 mM) and L-leucine (75-200 microM) act synergistically in stimulating GDH activity. GTP exerts a powerful inhibitory effect (IC(50) = 0.20 mM) on the housekeeping GDH; in contrast, the nerve tissue isoenzyme is resistant to GTP inhibition. Thus, although the housekeeping GDH is regulated primarily by GTP, the nerve tissue GDH activity depends largely on available ADP or L-leucine levels. Conditions associated with enhanced hydrolysis of ATP to ADP (e.g., intense glutamatergic transmission) are likely to activate nerve tissue-specific GDH leading to an increased glutamate flux through this pathway.

Feed restriction and genetic selection on the expression and activity of metabolism regulatory enzymes in rabbits

“…This can be explained by the fact that mammalian GDH is regulated allosterically by diverse compounds, such as purine nucleotides (ADP, NADH and GTP), and these are shown to influence the enzyme's activity rate as GDH is stimulated by ADP and inhibited by GTP, NADH and ATP. The oxidative deamination of glutamate by GDH induces the availability of the reduced coenzymes NADH or NADPH used in the synthesis of ATP, as can be observed in situations of energy shortage such as food restriction (Plaitakis and Zaganas, 2001).…”

Effects of hypoxia on the energy status and nitrogen metabolism of African lungfish during aestivation in a mucus cocoon

“…It is also known that two GDH isoforms (GLUD1 and GLUD2) exist in Homo sapiens (Plaitakis and Zaganas 2001). Additionally, there are two distinct forms of GDH with diVerent aYnities for glutamate, ammonia and -ketoglutarate in Richardson's ground squirrel, S. richardsonii, and entry into hibernation leads to changes in the properties of GDH that enables it to function optimally to suit the environment (Thatcher and Storey 2001).…”

Disturbance of Cultured Rat Neuronal Network Activity Depends on Concentration and Ratio of Leucine and α-Ketoisocaproate: Implication for Acute Encephalopathy of Maple Syrup Urine Disease

“…Leucine could stimulate the activity of glutamate dehydrogenase, which may be followed by a reduction of the cytosolic or vesicular transmitter glutamate pool (17). However, an increase of leucine enhances the glutamate concentration by donating amino groups and the glutamate is metabolized to the inhibitory neurotransmitter GABA (18).…”