Metabolism of Ammonia

METABOLISM OF AMMONIA

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 level of ammonia in the blood must be kept very low, because even slightly elevated concentrations (hyperammonemia) are toxic to the central nervous system (CNS). Therefore, there must be a metabolic mechanism by which nitrogen is moved from peripheral tissues to the liver for ultimate disposal as urea, at the same time maintaining low levels of circulating ammonia.

A. Sources of ammonia

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 aminotransferase and glutamate dehydrogenase reactions), producing ammonia. [Note: Liver catabolizes straight-chain amino acids, primarily.] However, substantial amounts of ammonia can be obtained from other sources.

1. From glutamine: An important source of plasma glutamine is from the catabolism of branched-chain amino acids in skeletal muscle. This glutamine is taken up by cells of the intestine, the liver, and the kidney. The liver and kidneys generate ammonia from glutamine by the actions of glutaminase (Figure 19.17) and glutamate dehydrogenase. 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 glutamate dehydrogenase, is a glucogenic precursor in liver and kidney.] Ammonia is also generated by intestinal glutaminase. The intestinal mucosal cells 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 19.17 Hydrolysis of glutamine to form ammonia (NH3).

2. From bacterial action in the intestine: 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. From 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. From purines and pyrimidines: In the catabolism of purines and pyrimidines, amino groups attached to the ring atoms are released as ammonia (see Figure 22.15).

B. Transport of ammonia 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 or alanine, rather than as free ammonia (see Figure 19.13).

Figure 19.13 Transport of ammonia (NH3) from muscle to the liver. ADP = adenosine diphosphate; Pi = inorganic phosphate; CoA = coenzyme A.

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.

U2. Glutamine: This amide of glutamate provides a nontoxic storage and transport form of ammonia (Figure 19.18). The ATP-requiring formation of glutamine from glutamate and ammonia by glutamine synthetase occurs primarily in skeletal muscle and 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 and the urea cycle in periportal (close to inflow of blood) hepatocytes and via glutamine synthetase as an ammonia “scavenger” in the perivenous hepatocytes.] The metabolism of ammonia is summarized in Figure 19.19.

Figure 19.18 Synthesis of glutamine. ADP = adenosine diphosphate; Pi = inorganic phosphate.

Figure 19.19 Metabolism of ammonia (NH₃). [Note: Glutamate dehydrogenase is one of several sources of NH₃.] Urea content in the urine is reported as urinary urea nitrogen, or UUN. Urea in blood is reported as BUN (blood urea nitrogen). The enzymes glutamate dehydrogenase, glutamine synthetase, and carbamoyl phosphate synthetase I fix NH₃ into organic molecules.

C. Hyperammonemia

The capacity of the hepatic urea cycle exceeds the normal rates of ammonia generation, and the levels of serum ammonia are normally low (5–35 µmol/l). However, when liver function is compromised, due either to genetic defects of the urea cycle or liver disease, blood levels can rise above 1,000 µmol/l. Such hyperammonemia is a medical emergency, because ammonia has a direct neurotoxic effect on the CNS. For example, elevated concentrations of ammonia in the blood cause the symptoms of ammonia intoxication, which include tremors, slurring of speech, somnolence (drowsiness), vomiting, cerebral edema, and blurring of vision. At high concentrations, ammonia can cause coma and death. There are two major types of hyperammonemia.

1. Acquired hyperammonemia: Liver disease is a common cause of hyperammonemia in adults and may be due, for example, to viral hepatitis or to hepatotoxins such as alcohol. Cirrhosis of the liver may result in formation of collateral circulation around the liver. As a result, portal blood is shunted directly into the systemic circulation and does not have access to the liver. Therefore, the conversion of ammonia to urea is severely impaired, leading to elevated levels of ammonia.

2. Congenital hyperammonemia: Genetic deficiencies of each of the five enzymes of the urea cycle have been described, with an overall incidence estimated to be 1:25,000 live births. X-linked ornithine transcarbamoylase deficiency is the most common of these disorders, predominantly affecting males, although female carriers may become symptomatic. All of the other urea cycle disorders follow an autosomal-recessive inheritance pattern. In each case, the failure to synthesize urea leads to hyperammonemia during the first weeks following birth. [Note: The hyperammonemia seen with arginase deficiency is less severe because arginine contains two waste nitrogens and can be excreted in the urine.] Historically, urea cycle defects had high morbidity (neurologic manifestations) and mortality. Treatment included restriction of dietary protein in the presence of sufficient calories to prevent catabolism. Administration of compounds that bind covalently to amino acids, producing nitrogen-containing molecules that are excreted in the urine, has improved survival. For example, phenylbutyrate given orally is converted to phenylacetate. This condenses with glutamine to form phenylacetylglutamine, which is excreted (Figure 19.20).

Figure 19.20 Treatment of patients with urea cycle defects by administration of phenylbutyrate to aid in excretion of ammonia (NH₃).