Urea cycle

Urea cycle is a series of biochemical reactions that produces urea from ammonia. This cycle occurs in ureotelic organisms. The urea cycle was the first metabolic cycle to be discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. This cycle is also known as the ornithine cycle.

Overview

The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH4+ and one from Aspartate, and a carbon atom from HCO3-, to the relatively nontoxic excretion product urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP).

Reactions

The reactions of the cycle are as follows:

1. Carbamoyl phosphate synthetase I (CPS1) catalyzes the condensation of ammonia and bicarbonate to form carbamoyl phosphate. This is the rate-limiting step of the urea cycle. The reaction requires two molecules of ATP, one of which is hydrolyzed to AMP and pyrophosphate.

2. Ornithine transcarbamylase (OTC) catalyzes the condensation of ornithine and carbamoyl phosphate to form citrulline, with the release of phosphate.

3. Argininosuccinate synthetase (ASS) catalyzes the condensation of citrulline and aspartate to form argininosuccinate, with the release of AMP and pyrophosphate. This reaction is driven to completion by the hydrolysis of the pyrophosphate, catalyzed by inorganic pyrophosphatase.

4. Argininosuccinate lyase (ASL) catalyzes the cleavage of argininosuccinate to form arginine and fumarate.

5. Arginase (ARG1) catalyzes the hydrolysis of arginine to form ornithine and urea. The ornithine is transported back to the mitochondria to begin the cycle again.

Regulation

The urea cycle is regulated at two levels. The first level of regulation is by substrate availability. If there is an excess of dietary protein, then there will be an increase in the amino acids that are metabolized to form urea. The second level of regulation is through allosteric regulation. N-acetylglutamate is an essential allosteric activator of CPS1 in mammals, and it is produced from glutamate and acetyl-CoA by the enzyme N-acetylglutamate synthase (NAGS). NAGS is activated by arginine, so when dietary protein is high, arginine concentrations increase, stimulating the production of N-acetylglutamate, which in turn activates CPS1 and the urea cycle.

Clinical significance

Deficiencies in the enzymes of the urea cycle lead to urea cycle disorders (UCDs). UCDs are a group of rare genetic disorders that affect the body's ability to get rid of ammonia. Symptoms of UCDs include a decreased level of consciousness, poor feeding, vomiting, seizures, and coma. These disorders are usually diagnosed in infancy and early childhood.

See also

• Amino acid metabolism
• Ammonia
• Urea
• Urea cycle disorder
• Hans Adolf Krebs
• Kurt Henseleit

References

Urea cycle Resources
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