Oxidative Deamination

1. 1

   L-glutamate + NAD⁺ (or NADP⁺) + H₂O ⇌ α-ketoglutarate + NH₄⁺ + NADH (or NADPH) + H⁺

   Glutamate dehydrogenase 1.4.1.3 ST-0138 Reversible NAD+ NADH NADP+ NADPH H2O
   In Glutamate NAD+ (or NADP+) H2O

   Out Alpha-ketoglutarate NH4+ NADH (or NADPH) H+
   › Notes

   Glutamate dehydrogenase catalyzes oxidative deamination in the mitochondrial matrix. NAD⁺ is generally the major oxidant during net hepatic glutamate oxidation, although the enzyme can use NADP⁺; the reaction is reversible and is the principal regulated route for release of free ammonia from glutamate.

2. 2

   L-glutamine + H₂O → L-glutamate + NH₄⁺

   Glutaminase 3.5.1.2 ST-0139 Irreversible H2O
   In Glutamine H2O

   Out Glutamate NH4+
   › Notes

   Glutaminase hydrolyzes the amide nitrogen of glutamine in mitochondria; it requires water but no redox cofactor. This irreversible hydrolytic deamidation is not itself oxidative deamination, but it is a major upstream source of mitochondrial glutamate and ammonia in liver, kidney, intestine, and brain.

3. 3

   L-asparagine + H₂O → L-aspartate + NH₄⁺

   Asparaginase 3.5.1.1 ST-0140 Irreversible H2O
   In Asparagine H2O

   Out Aspartate NH4+
   › Notes

   Asparaginase catalyzes irreversible deamidation, providing a smaller additional source of ammonia. The resulting aspartate can be transaminated to oxaloacetate and glutamate or can donate nitrogen to the urea cycle.

Showing all 3 steps.

Overview

Oxidative deamination releases the amino nitrogen of glutamate as ammonium while regenerating α-ketoglutarate. In the liver this provides mitochondrial ammonia for carbamoyl phosphate synthesis and the urea cycle; in kidney, ammonium production contributes to acid excretion. Coupling transamination to glutamate dehydrogenase creates the classic transdeamination route by which nitrogen from many amino acids is ultimately disposed of.

Cellular location

Glutamate dehydrogenase (GDH/GLUD) is a mitochondrial matrix enzyme, especially active in liver and kidney and present in brain and other oxidative tissues. Mitochondrial localization places generated NH₄⁺ adjacent to carbamoyl phosphate synthetase I in hepatocytes.

Net energetics

For net GDH oxidation with NAD⁺, one glutamate yields 1 NADH and one NH₄⁺, with no ATP consumed. If NADP⁺ is the acceptor, the reaction yields 1 NADPH instead; subsequent oxidative phosphorylation of NADH can capture energy if reducing equivalents are reoxidized.

Clinical significance

Free ammonia is neurotoxic, so oxidative deamination is tightly coupled to urea synthesis in periportal hepatocytes or to renal ammonium excretion. Activating GLUD1 variants cause hyperinsulinism/hyperammonemia syndrome, partly because leucine-stimulated GDH promotes insulin secretion and excess ammonia generation. Conversely, impaired hepatic ammonia detoxification in severe liver disease produces hyperammonemia and can contribute to hepatic encephalopathy.