Oxidative deamination: Amino group removal

In contrast to transamination reactions that transfer amino groups, oxidative deamination reactions result in the liberation of the amino group as free ammonia (Fig. 1). These reactions occur primarily in the liver and kidney. They provide α-keto acids that can enter the central pathways of energy metabolism and ammonia, which is a source of nitrogen in hepatic urea synthesis. [Note: Ammonia exists primarily as ammonium (NH₄⁺) in aqueous solution, but it is the unionized form (NH₃) that crosses membranes.]

Figure 1: Oxidative deamination by glutamate dehydrogenase. [Note: The enzyme is unusual in that it uses both NAD+ (nicotinamide adenine dinucleotide)  and NADPH (nicotinamide adenine dinucleotide phosphate).] NH3 = ammonia.

1. Glutamate dehydrogenase: As described above, the amino groups of most amino acids are ultimately funneled to glutamate by means of transamination with α-ketoglutarate. Glutamate is unique in that it is the only amino acid that undergoes rapid oxidative deamination, a reaction catalyzed by glutamate dehydrogenase ([GDH], see Fig. 1).

Therefore, the sequential action of transamination (resulting in the transfer of amino groups from most amino acids to α-ketoglutarate to produce glutamate) and the oxidative deamination of that glutamate  (regenerating α-ketoglutarate) provide a pathway whereby the amino groups of most amino acids can be released as ammonia.

a. Coenzymes: GDH, a mitochondrial enzyme, is unusual in that it can use either nicotinamide adenine dinucleotide (NAD⁺) or its phosphorylated reduced form (NADPH) as a coenzyme (see Fig 1). NAD⁺ is used primarily in oxidative deamination (the simultaneous loss of ammonia coupled with the oxidation of the carbon skeleton, as shown in Fig. 2A), whereas NADPH is used in reductive amination (the simultaneous gain of ammonia coupled with the reduction of the carbon skeleton, as shown in Fig. 2B).

Figure 2 A, B. Combined actions of aminotransferase and glutamate dehydrogenase reactions. [Note: Reductive amination occurs only when ammonia (NH₃) level is high.] NAD(H) = nicotinamide adenine dinucleotide;  NADP(H) = nicotinamide adenine dinucleotide phosphate.

b. Reaction direction: The direction of the reaction depends on the relative concentrations of glutamate, α-ketoglutarate, and ammonia and the ratio of oxidized to reduced coenzymes. For example, after ingestion of a meal containing protein, glutamate levels in the liver are elevated, and the reaction proceeds in the direction of amino acid degradation and the formation of ammonia (see Fig. 2A). High ammonia levels are required to drive the reaction to glutamate synthesis.

c. Allosteric regulators: Guanosine triphosphate is an allosteric inhibitor of GDH, whereas adenosine diphosphate is an activator. Therefore,  when energy levels are low in the cell, amino acid degradation by GDH is high, facilitating energy production from the carbon skeletons derived from amino acids.

2. d-Amino acid oxidase: D-Amino acids) are supplied by the diet but are not used in the synthesis of mammalian proteins. They are,  however, efficiently metabolized to α-keto acids, ammonia, and hydrogen peroxide in the peroxisomes of liver and kidney cells by flavin adenine dinucleotide–dependent D-amino acid oxidase (DAO). The α-keto acids can enter the general pathways of amino acid metabolism and be reaminated to L-isomers or catabolized for energy. [Note: DAO degrades D-serine, the isomeric form of serine that modulates N-methyl- D-aspartate (NMDA)-type glutamate receptors. Increased DAO activity has been linked to increased susceptibility to schizophrenia. DAO also converts glycine to glyoxylate).] L-Amino acid oxidases are found in snake venom.