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The Role of Glutamate Dehydrogenase in Mammalian Ammonia Metabolism

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Abstract

Glutamate dehydrogenase (GDH) catalyzes the reversible inter-conversion of glutamate to α-ketoglutarate and ammonia. High levels of GDH activity is found in mammalian liver, kidney, brain, and pancreas. In the liver, GDH reaction appears to be close-to-equilibrium, providing the appropriate ratio of ammonia and amino acids for urea synthesis in periportal hepatocytes. In addition, GDH produces glutamate for glutamine synthesis in a small rim of pericentral hepatocytes. Hence, hepatic GDH can be either a source for ammonia or an ammonia scavenger. In the kidney, GDH function produces ammonia from glutamate to control acidosis. In the human, the presence of two differentially regulated isoforms (hGDH1 and hGDH2) suggests a complex role for GDH in ammonia homeostasis. Whereas hGDH1 is sensitive to GTP inhibition, hGDH2 has dissociated its function from GTP control. Furthermore, hGDH2 shows a lower optimal pH than hGDH1. The hGDH2 enzyme is selectively expressed in human astrocytes and Sertoli cells, probably facilitating metabolic recycling processes essential for their supportive role. Here, we report that hGDH2 is also expressed in the epithelial cells lining the convoluted tubules of the renal cortex. As hGDH2 functions more efficiently under acidotic conditions without the operation of the GTP energy switch, its presence in the kidney may increase the efficacy of the organ to maintain acid base equilibrium.

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Abbreviations

GDH:

Glutamate dehydrogenase

PDG:

Phosphate dependent glutaminase

hGDH1:

Human glutamate dehydrogenase encoded by the GLUD1 gene

hGDH2:

Human glutamate dehydrogenase encoded by the GLUD2 gene

HI/HA:

Hyperinsulinism/hyperammonemia

TCA cycle:

Tricarboxylic acid cycle

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Acknowledgment

This study was supported by the Association for the Advancement of Research and Treatment of Neurologic Disorders of Crete≪EY ZHN≫. We thank Ioannis Zaganas for his contribution to developing the anti-hGDH2 specific antibody.

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  1. Department of Neurology, Medical School, University of Crete, Voutes, 71003, Heraklion, Crete, Greece

    Cleanthe Spanaki & Andreas Plaitakis

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  1. Cleanthe Spanaki
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  2. Andreas Plaitakis
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Correspondence to Cleanthe Spanaki.

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Spanaki, C., Plaitakis, A. The Role of Glutamate Dehydrogenase in Mammalian Ammonia Metabolism. Neurotox Res 21, 117–127 (2012). https://doi.org/10.1007/s12640-011-9285-4

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