Ammonia is a universal participant in amino acid synthesis and degradation, but its accumulation has toxic consequences. Because terrestrial animals must conserve water, they convert ammonia to a form that can be excreted without large water losses. Birds, terrestrial reptiles, and insects convert most of their excess ammonia to uric acid, an oxidized purine. Most mammals excrete the bulk of their nitrogen as urea. See urea cycle reactions here.

Urea is synthesized in mammals almost exclusively in the liver and then transported to the kidneys for excretion. The process that generates urea is called the urea cycle and is depicted in Figure 20.13. The last step in the cycle is the hydrolytic cleavage of arginine to yield ornithine and one molecule of urea. Virtually all organisms use the reactions shown in Figure 20.13 to synthesize arginine from ornithine, but they lack the arginase enzyme needed to make the pathway cyclic. Only ureotelic organisms-those that excrete urea-contain arginase, so only ureotelic organisms can carry out the cyclic pathway.

The net reaction for one turn of the urea cycle is

CO2 + NH4⁺ + 3 ATP + Aspartate + 2H2O -> Urea + 2 ADP + 2 Pi +AMP + PPi + Fumarate

Because it takes 2 ATP to regenerate one ATP from one AMP, four high energy phosphates are consumed in each turn of the cycle. Thus, synthesis of urea is energetically expensive.

Reactions of the urea cycle occur in both the mitochondria and cytosol of liver cells. Glutamate dehydrogenase, the citric acid cycle enzymes, carbamoyl phosphate synthetase I, and ornithine transcarbamoylase are localized in the mitochondrion, whereas the rest of the cycle occurs in the cytosol. This means that ornithine must be transported into mitochondria, and citrulline must be exported to the cytosol, in order for the cycle to proceed.

Following synthesis, urea is transported in the bloodstream to the kidneys, which filter it for excretion. Measurements of blood urea nitrogen (BUN) levels provide a sensitive clinical test of kidney function, because filtration and removal of urea are impaired in cases of kidney malfunction. Analogously, blood ammonia measurements are a sensitive test of liver function.