Urea Cycle

Unlike glucose, there is no storage form of amino acids. Amino acids are degraded into free ammonia (NH4+) and the carbon skeleton. Living organisms excrete excess nitrogen as ammonia, uric acid, and urea.

Living organisms excrete excess nitrogen as ammonia, uric acid, and urea. The urea cycle takes place in the mitochondria and the cytosol. There are four enzymes involved, three of which are cytosolic and one is mitochondrial. In the mitochondria, carbamoyl phosphate is catalyzed by carbamoyl phosphate synthetase (CPS I). Carbamoyl phosphate is formed by condensing and activating bicarbonate and ammonia. Two ATP is also required. It is the first acquisition of nitrogen.  The carbamoyl group of carbamoyl phosphate is transferred to ornithine giving citrulline. The reaction is catalyzed by ornithine transcarbamoylase. Citrulline is then transported out to the cytosol. Now in the cytosol, citrullyl-AMP is formed. Adding aspartate displaces AMP to form argininosuccinate, where urea’s second nitrogen is acquired. It is catalyzed by argininosuccinate synthetase. Arginine, urea’s immediate precursor, is then made by the expulsion of fumarate from argininosuccinate catalyzed by argininosuccinase. In the final reaction, urea is formed by cleaving off the carbon backbone of arginine by arginase. Ornithine is also made, which is transported back into the mitochondria. Fumarate from argininosuccinate is converted to aspartate for reuse in the argininosuccinate synthetase reaction.  The formation of urea costs more than three high energy bonds. The urea cycle ultimately yield 6 ATPs. 

Urea catabolism is regulated on two levels. During prolonged starvation, muscle proteins are broken down to supply energy, therefore production of urea increases significantly. The enzymes involved in the urea cycle are also synthesized at higher rates.

In the short term, CPS I is allosterically regulated. CPS I is allosterically activated by N-acetylglutamate, which is synthesized from acetyl-CoA and glutamate by N-acetylglutamate synthase. The steady-state levels of N-acetylglutamate are determined by the concentrations of glutamate and acetyl-CoA (the substrates for N-acetylglutamate synthase) and arginince (an activator of N-acetylglutamate synthase), and tus an activator of the urea cycle).