The Urea Cycle

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea ((NH2)2CO) from ammonia (NH3). This cycle was the first metabolic cycle discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.

 
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn errors of metabolism), and in liver failure. The result of liver failure is an accumulation of nitrogenous waste, mainly ammonia, which leads to hepatic encephalopathy.

The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH4+ and one from Asp, 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). Ornithine is the carrier of these carbon and nitrogen atoms.

In the first reaction, NH4+ + HCO3− is equivalent to NH3 + CO2 + H2O.

Thus, the overall equation of the urea cycle is: shown in the diagram.

NH3 + CO2 + aspartate + 3 ATP + 2 H2O → urea + fumarate + 2 ADP + 2 Pi + AMP + PPi
Since fumarate is obtained by removing NH3 from aspartate (by means of reactions 3 and 4), and PPi + H2O → 2 Pi, the equation can be simplified as follows:

2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP
Note that reactions related to the urea cycle also cause the production of 2 NADH, so the urea cycle releases slightly more energy than it consumes. This NADH is produced in two ways:

One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and α-ketoglutarate. Glutamate is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.

The fumarate released in the cytosol is converted to malate by cytosolic fumarase. This malate is then converted to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol. Oxaloacetate is one of the keto acids that are preferred by transaminases, and so will be recycled to aspartate, maintaining the flow of nitrogen into the urea cycle.

The two NADH produced can provide energy for the formation of 4 ATP (cytosolic NADH provides only 1.5 ATP due to the glycerol-3-phosphate shuttle who transfers the electrons from cytosolic NADH to FADH2 and that gives 1.5 ATP), net production of one high-energy phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.

The fate of oxaloacetate is either to produce aspartate via transamination or to be converted to phosphoenolpyruvate, which is a substrate for gluconeogenesis.