23.3:
Urea Cycle
The urea cycle is the primary way that mammals eliminate ammonia, a nitrogenous waste product of protein catabolism, from the body through the conversion to urea, which is accomplished by cells in the liver.
Starting in the cellular mitochondria, ammonia is first changed to the compound carbamoyl phosphate, using bicarbonate, energy in the form of ATP, and the enzyme carbamoyl phosphate synthetase 1.
Next, the enzyme ornithine transcarbamylase combines carbamoyl phosphate and the amino acid ornithine into citruline which is transferred to the cytosol.
In this third step, citruline combines with aspartate to form arginosuccinate. This reaction is an enzymatic one governed by arginosuccinate synthetase, and requires a large amount of energy by converting ATP to AMP.
Arginosuccinate is then cleaved into arginine and fumarate by the enzyme arginosuccinate lyase.
In the final step, the enzyme arginase 1 splits arginine into urea and ornithine. Urea is ultimately excreted by the kidneys. Ornithine goes back to the mitochondria to participate in the urea cycle again.
23.3:
Urea Cycle
The urea cycle describes how liver cells convert ammonia to urea. Ammonia is a toxic waste product of protein catabolism. Land animals must convert ammonia into the less toxic urea which can be safely eliminated by the kidneys through urine. Marine animals excrete ammonia directly, and the surrounding water dilutes the ammonia to safe levels.
There are five basic steps in the urea cycle:
- the conversion of ammonia (NH3) to carbamoyl phosphate
- the introduction of ornithine in the transformation of carbamoyl phosphate to citrulline
- the transformation of citrulline into arginosuccinate involving aspartate and chemical energy (ATP)
- the conversion of arginosuccinate into arginine with fumarate as a by-product
- the formation of urea and ornithine from arginine
Notice that ornithine is used in the second step and is regenerated in the last step. Since ornithine is recycled, the urea cycle is sometimes referred to as the ornithine cycle.
Elevated levels of blood ammonia, or hyperammonemia, results from an interruption of the urea cycle. This can occur at the organ level where scar tissue blocks the blood supply to the liver. Scar tissue, or cirrhosis, can result from chronic alcohol abuse, hepatitis B, or hepatitis C infection.
Within the liver cells, disruption of the urea cycle can also occur in any one of its five steps. Ornithine transcarbamylase deficiency (OTCD) is an inherited metabolic disorder that results in a full or partial enzyme deficiency in step 2, affecting the production of citrulline from ornithine and carbamoyl phosphate.
Hyperammonemia in adults, resulting from cirrhosis or late-onset metabolic disorders, can result in deficits in attention and other cognitive impairments. They are also at higher risk of death from liver failure. In neonates with early-onset enzyme deficiency, developmental delays can be expected. If not diagnosed and treated, these infants risk coma and death. How elevated ammonia damages the brain to produce cognitive and developmental delays is not yet fully understood; however, disturbances in amino acid and neurotransmitter levels, disruptions in ion channel function, and energy deficits in the brain have been proposed as possible mechanisms.
Suggested Reading
Batshaw, Mark L., Mendel Tuchman, Marshall Summar, and Jennifer Seminara. “A Longitudinal Study of Urea Cycle Disorders.” Molecular Genetics and Metabolism 113, no. 0 (2014): 127–30. [Source]