Aminotransferases are enzymes that are normally found within cells. When they are found in the plasma at low levels, it indicates the release of cellular contents during regular cell turnover. Elevated levels of aminotransferases in the plasma suggest damage to cells that contain these enzymes. Conditions like physical trauma or diseases can cause cell lysis, leading to the release of intracellular enzymes into the blood. Two specific aminotransferases, AST and ALT, are of particular importance in diagnosis when they are present in the plasma.

Hepatic diseases result in elevated levels of AST and ALT in the plasma, with more extensive cell necrosis leading to higher levels. Severe viral hepatitis, toxic injury, and prolonged circulatory collapse are examples of conditions that cause significant cell damage and therefore result in elevated levels of AST and ALT. ALT is more specific to liver disease, while AST is more sensitive due to its larger concentration in the liver. Measuring AST and ALT levels serially can be useful in determining the progression of liver damage. Figure 19.10 illustrates the early release of ALT into the blood after ingesting a liver toxin. Additionally, liver damage decreases the hepatic conjugation and excretion of bilirubin, leading to an elevation in its levels.

Aminotransferases may also be elevated in nonhepatic diseases that cause damage to cardiac or skeletal muscle. However, these disorders can usually be differentiated clinically from liver disease.

Oxidative deamination reactions, unlike transamination reactions, result in the liberation of the amino group as free ammonia. These reactions primarily occur in the liver and kidney and provide α-keto acids that can enter the central pathways of energy metabolism, as well as ammonia, which serves as a source of nitrogen in hepatic urea synthesis. Glutamate dehydrogenase is the enzyme responsible for the rapid oxidative deamination of glutamate. Most amino acids undergo transamination with α-ketoglutarate to produce glutamate, which is then oxidatively deaminated by glutamate dehydrogenase, regenerating α-ketoglutarate. This sequential action of transamination and oxidative deamination allows the release of amino groups from most amino acids as ammonia.

Glutamate dehydrogenase can use either nicotinamide adenine dinucleotide (NAD+) or its phosphorylated reduced form (NADPH) as a coenzyme. NAD+ is primarily used in oxidative deamination, where ammonia is lost simultaneously with the oxidation of the carbon skeleton. On the other hand, NADPH is used in reductive amination, where ammonia is gained simultaneously with the reduction of the carbon skeleton.
Diagnostic value: Aminotransferases are normally intracellular enzymes, with the low levels found in the plasma representing the release of cellular contents during normal cell turnover. Elevated plasma levels of aminotransferases indicate damage to cells rich in these enzymes. For example, physical trauma or a disease process can cause cell lysis, resulting in release of intracellular enzymes into the blood. Two aminotransferases, AST and ALT, are of particular diagnostic value when they are found in the plasma.
a.
Hepatic disease: Plasma AST and ALT are elevated in nearly all hepatic diseases but are particularly high in conditions that cause extensive cell necrosis, such as severe viral hepatitis, toxic injury, and prolonged circulatory collapse. ALT is more specific than AST for liver disease, but the latter is more sensitive because the liver contains larger amounts of AST. Serial measurements of AST and ALT (liver function tests) are often useful in determining the course of liver damage. Figure 19.10 shows the early release of ALT into the blood, following ingestion of a liver toxin. [Note: The elevation in bilirubin results from hepatocellular damage that decreases the hepatic conjugation and excretion of bilirubin (see p. 282).] b.
Nonhepatic disease: Aminotransferases may be elevated in nonhepatic diseases such as those that cause damage to cardiac or skeletal muscle. However, these disorders can usually be distinguished clinically from liver disease.
B. 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. 19.11). 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.] 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. 19.11). 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. 19.11). NAD+ is used primarily in oxidative deamination (the simultaneous loss of ammonia coupled with the oxidation of the carbon skeleton, as shown in Fig. 19.12A), whereas NADPH is used in reductive amination (the simultaneous gain of ammonia coupled with the reduction of the carbon skeleton, as shown in Fig. 19.12B).
NADP(H) = nicotinamide adenine dinucleotide phosphate.
b.