Ammonia Metabolism

Ammonia is produced by all tissues during the metabolism of a variety of compounds, and it is disposed of primarily by formation of urea in the liver.  However, the blood ammonia level must be kept very low, because even slightly elevated concentrations (hyperammonemia) are toxic to the central nervous system (CNS). Therefore, a mechanism is required for the transport of nitrogen from the peripheral tissues to the liver for ultimate disposal as urea while keeping circulating levels of free ammonia low.

A. Sources

Amino acids are quantitatively the most important source of ammonia because most Western diets are high in protein and provide excess amino acids, which travel to the liver and undergo transdeamination (that is, the linking of the aminotransferase and GDH reactions), producing ammonia.  [Note: The liver catabolizes straight-chain amino acids, primarily.]  However, substantial amounts of ammonia can be obtained from other sources.

1. Glutamine: An important source of plasma glutamine is from the catabolism of BCAA in skeletal muscle. This glutamine is taken up by cells of the intestine, the liver, and the kidneys. The liver and kidneys generate ammonia from glutamine by the actions of glutaminase (Fig. 1) and GDH. In the kidneys, most of this ammonia is excreted into the urine as NH4+, which provides an important mechanism for maintaining the body’s acid–base balance through the excretion of protons. In the liver, the ammonia is detoxified to urea and excreted.

[Note: α-Ketoglutarate, the second product of GDH, is a glucogenic precursor in the liver and kidneys.] Ammonia is also generated by intestinal glutaminase. Enterocytes obtain glutamine either from the blood or from digestion of dietary protein. [Note: Intestinal glutamine metabolism also produces alanine, which is used by the liver for gluconeogenesis, and citrulline, which is used by the kidneys to synthesize arginine.]

Figure 1:  Hydrolysis of glutamine to form ammonia (NH3).

2. Intestinal bacteria: Ammonia is formed from urea by the action of bacterial urease in the lumen of the intestine. This ammonia is absorbed from the intestine by way of the portal vein, and virtually all is removed by the liver via conversion to urea.

3. Amines: Amines obtained from the diet and monoamines that serve as hormones or neurotransmitters give rise to ammonia by the action of monoamine oxidase.

4. Purines and pyrimidines: In the catabolism of purines and pyrimidines,  amino groups attached to the ring atoms are released as ammonia.

B. Transport in the circulation

Although ammonia is constantly produced in the tissues, it is present at very low levels in blood. This is due both to the rapid removal of blood ammonia by the liver and to the fact that several tissues, particularly muscle, release amino acid nitrogen in the form of glutamine and alanine, rather than as free ammonia.

1. Urea: Formation of urea in the liver is quantitatively the most important disposal route for ammonia. Urea travels in the blood from the liver to the kidneys, where it passes into the glomerular filtrate.

2. Glutamine: This amide of glutamate provides a nontoxic storage and transport form of ammonia (Fig. 2). The ATP-requiring formation of glutamine from glutamate and ammonia by glutamine synthetase occurs primarily in skeletal muscle and the liver but is also important in the CNS, where it is the major mechanism for the removal of ammonia in the brain. Glutamine is found in plasma at concentrations higher than other amino acids, a finding consistent with its transport function. [Note: The liver keeps blood ammonia levels low through glutaminase, GDH, and the urea cycle in periportal (close to inflow of blood) hepatocytes and through glutamine synthetase as an ammonia scavenger in the perivenous hepatocytes.] Ammonia metabolism is summarized in Figure 3.

Figure 2: Synthesis of glutamine. ADP = adenosine diphosphate; Pi = inorganic phosphate; NH3 = ammonia.

Figure 3: Ammonia (NH3) metabolism. Urea content in the urine is reported as urinary urea nitrogen, or UUN. Urea in blood is reported as BUN (blood urea nitrogen). [Note: The enzymes glutamate dehydrogenase, glutamine synthetase,  and carbamoyl phosphate synthetase I fix NH3 into organic molecules.]