The urea cycle (also known as the ornithine cycle) is a cycle of
ureotelic
.
The urea cycle converts highly toxic ammonia to urea for excretion.
TCA cycle. This cycle was described in more detail later on by Ratner and Cohen. The urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys
.
Function
Amino acid catabolism results in waste ammonia. All animals need a way to excrete this product. Most aquatic organisms, or ammonotelic organisms, excrete ammonia without converting it.[1] Organisms that cannot easily and safely remove nitrogen as ammonia convert it to a less toxic substance, such as urea, via the urea cycle, which occurs mainly in the liver. Urea produced by the liver is then released into the bloodstream, where it travels to the kidneys and is ultimately excreted in urine. The urea cycle is essential to these organisms, because if the nitrogen or ammonia is not eliminated from the organism it can be very detrimental.[2] In species including birds and most insects, the ammonia is converted into uric acid or its urate salt, which is excreted in solid form
. Further, the urea cycle consumes acidic waste carbon dioxide by combining it with the basic ammonia, helping to maintain a neutral pH.
Reactions
The entire process converts two amino groups, one from NH+ 4 and one from
Before the urea cycle begins ammonia is converted to carbamoyl phosphate. The reaction is catalyzed by carbamoyl phosphate synthetase I and requires the use of two ATP molecules.[1] The carbamoyl phosphate then enters the urea cycle.
Steps of the urea cycle
Carbamoyl phosphate is converted to citrulline. With catalysis by ornithine transcarbamylase, the carbamoyl phosphate group is donated to ornithine and releases a phosphate group.[1]
Arginine is cleaved by arginase to form urea and ornithine. The ornithine is then transported back to the mitochondria to begin the urea cycle again.[1][4]
Overall reaction equation
In the first reaction, NH+ 4 + HCO− 3 is equivalent to NH3 + CO2 + H2O.
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:
Note that reactions related to the urea cycle also cause the production of 2
NADH
, so the overall reaction releases slightly more energy than it consumes. The NADH is produced in two ways:
One NADH molecule is produced by the enzyme
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 hydrated to
aspartate
, maintaining the flow of nitrogen into the urea cycle.
We can summarize this by combining the reactions:
CO2 +
oxaloacetate
+ 2 ADP + 2 Pi + AMP + PPi + 2 NADH
The two NADH produced can provide energy for the formation of 5
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.
Products of the urea cycle
As stated above many vertebrates use the urea cycle to create urea out of ammonium so that the ammonium does not damage the body. Though this is helpful, there are other effects of the urea cycle. For example: consumption of two ATP, production of urea, generation of H+, the combining of HCO−3 and NH+4 to forms where it can be regenerated, and finally the consumption of NH+4.[6]
Regulation
N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of
CPS1. NAcGlu is an obligate activator of carbamoyl phosphate synthetase.[7] Synthesis of NAcGlu by N-acetylglutamate synthase (NAGS) is stimulated by both Arg, allosteric stimulator of NAGS, and Glu, a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when free amino acids
are elevated. So Glu not only is a substrate for NAGS but also serves as an activator for the urea cycle.
Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in cycle enzymes other than
ARG1
do not result in significant decreases in urea production (if any cycle enzyme is entirely missing, death occurs shortly after birth). Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the way back up the cycle to NH+ 4, resulting in hyperammonemia (elevated [NH+ 4]P).
Although the root cause of NH+ 4 toxicity is not completely understood, a high [NH+ 4] puts an enormous strain on the NH+ 4-clearing system, especially in the
The urea cycle and the citric acid cycle are independent cycles but are linked. One of the nitrogen atoms in the urea cycle is obtained from the transamination of oxaloacetate to aspartate.[8] The fumarate that is produced in step three is also an intermediate in the citric acid cycle and is returned to that cycle.[8]
Urea cycle disorders
Urea cycle disorders are rare and affect about one in 35,000 people in the
brain damage.[2] New-borns with UCD are at a much higher risk of complications or death due to untimely screening tests and misdiagnosed cases. The most common misdiagnosis is neonatal sepsis. Signs of UCD can be present within the first 2 to 3 days of life, but the present method to get confirmation by test results can take too long.[10] This can potentially cause complications such as coma or death.[10]
Urea cycle disorders may also be diagnosed in adults, and symptoms may include delirium episodes, lethargy, and symptoms similar to that of a stroke.[11] On top of these symptoms, if the urea cycle begins to malfunction in the liver, the patient may develop cirrhosis.[12] This can also lead to sarcopenia (the loss of muscle mass).[12] Mutations lead to deficiencies of the various enzymes and transporters involved in the urea cycle, and cause urea cycle disorders.[1] If individuals with a defect in any of the six enzymes used in the cycle ingest amino acids beyond what is necessary for the minimum daily requirements, then the ammonia that is produced will not be able to be converted to urea. These individuals can experience hyperammonemia, or the build-up of a cycle intermediate.
Urea cycle.
Urea cycle colored.
Grey nodes: vitamin and cofactor metabolism. 
Brown nodes: nucleotide and protein metabolism. 
Green nodes: lipid metabolism