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'''Glutamate Dehydrogenase''' (GDH) is a homohexameric enzyme found in most microbes and eukaryotes that catalyses the reversible oxidative deamination of L-glutamate to α-ketoglutarate, and vice versa using NAD+ and/or NADP+ as cofactos. Located in the mitochondria, GDH plays a key role in urea synthesis, nitrogen and glutamate (Glu) metabolism, and the energy homeostasis. In humans, GDH is expressed at high levels in the liver, brain, pancreas and kidney. Acting as an oxidoreductase (Enzyme Class I) , GDH catalyzes the reversible NAD (P)+-linked oxidative deamination of L-glutamate into alpha ketoglutarate and ammonia in two steps. The first step involves a Schiff base intermediate being formed between ammonia and alpha ketoglutarate.  This Schiff base intermediate establishes the alpha carbon atom in glutamate’s stereochemistry.  The second step involves the Schiff base intermediate being protonated, which is done by the transfer of a hydride ion from NADPH resulting in L-glutamate.  In it's mechanism, GDH is unique because it is able to utilize both NAD+ and NADP+ <ref>Stryer (Ed.). Biochemistry (5th Ed.) 2002. W.H. Freeman and Company, New York.</ref>.  NADP+ is utilized in the forward reaction of alpha ketogluterate and free ammonia, which are converted to L-glutamate via a hydride transfer from NADPH to glutamate (15).  NAD+ is utilized in the reverse reaction, which involves L-glutamate being converted to alpha ketoglutarate and free ammonia via an oxidative deamination reaction <ref>PMID:9405044</ref>.  The extensive production of ammonia by peripheral tissue or glutamate dehydrogenase is not allowed because of the highly toxic effects of circulating ammonia in cells.  As a result, the ammonia produced in the reverse reaction of GDH is excreted as NH4+ in the urine, by first going through the urea cycle.

*<scene name='56/564037/Gtp/1'>GTP</scene>is a potent inhibitor (red) for the reaction of GDH (yellow) that binds at the base of the antenna, wedged in between the NAD binding domain and the pivot helix. This binding site is only available for GTP binding when the catalytic cleft is closed. Therefore, after GTP binds to the 'closed' conformation it is more difficult for the 'mouth' to open and release either NAD+ and NADP+ as coenzyme <ref>D'Mello, J. P. F.. "Glutamate Dehydrogenase." Amino Acids in Human Nutrition and Health. 2012. 1-23. Print</ref>.  

*Inhibition by high [ADP] is due to competition between ADP and the adenosine moiety of the coenzyme at the active site 1 <ref>D'Mello, J. P. F.. "Glutamate Dehydrogenase." Amino Acids in Human Nutrition and Health. 2012. 1-23. Print</ref>.

[[Image:Implications.jpg|frame|left|Figure 5. This schematic shows how the loss GTP inhibition can cause the hyperstimulated secretion of insulin (top) and the elevated serum levels of ammonium (bottom). In the pancreas, the loss of GTP inhibition increases the flux of glutamate to the Krebs cycle, leading to elevated ATP levels and secretion of insulin. In the liver, not only does accelerated catabolism increase the levels of ammonium, but the lower levels of glutamate also decrease the production of N-acetylglutamate.]] Hyperosmolar hyperglycemic state (HHS), a complication of diabetes 2, in which high blood sugars can cause severe dehydration, coma, or death, was one of the first diseases that clearly linked GDH regulation to insulin and ammonia homeostasis. Recent studies have demonstrated that the activation of GDH it tightly correlated with increased glutaminolysis and release of insulin. HHS syndrome is caused by the loss of GTP regulation of GDH. Children with HHS have increased β-cell responsiveness and susceptibility to hypoglycemia following high protein meals due to uncontrolled catabolism of amino acids yielding high ATP levels that stimulate insulin secretion and high serum levels of ammonium. This elevation of serum ammonia levels induces an altered regulation of GDH, leading to increased ammonia production from glutamate oxidation. In addition to that, it can cause impaired urea synthesis by carbmoylphosphate synthetase (CPS) due to reduced formation of N-actyl-glutamate (activator) from glutamate (figure 4). This genetic lesion disrupts the regulator linkage between glycolysis and amino acid catabolism. <ref>D'Mello, J. P. F.. "Glutamate Dehydrogenase." Amino Acids in Human Nutrition and Health. 2012. 1-23. Print</ref>.