Urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of
The urea cycle converts highly toxic ammonia to urea for excretion..
Function
Reactions
The entire process converts two amino groups, one from NH+
4 and one from
Step | Reactants | Products | Catalyzed by | Location |
---|---|---|---|---|
1 | NH3 + HCO− 3 + 2ATP |
carbamoyl phosphate + 2ADP + Pi | CPS1 | mitochondria |
2 | carbamoyl phosphate + ornithine | citrulline + Pi | OTC, zinc, biotin | mitochondria |
3 | citrulline + aspartate + ATP | ASS |
cytosol | |
4 | argininosuccinate |
fumarate |
ASL | cytosol |
5 | arginine + H2O | ornithine + urea | ARG1 , manganese |
cytosol |
- The reactions of the urea cycle
1 L-
First reaction: entering the urea cycle
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]
- A condensation reaction occurs between the amino group of aspartate and the carbonyl group of citrulline to form argininosuccinate. This reaction is ATP dependent and is catalyzed by argininosuccinate synthetase.[1]
- Argininosuccinate undergoes cleavage by fumarate.[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.
Thus, the overall equation of the urea cycle is:
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
- One NADH molecule is produced by the enzyme Glutamateis 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
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
Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in cycle enzymes other than
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
Link with the citric acid cycle
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
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.
Individual disorders
- N-Acetylglutamate synthase (NAGS) deficiency
- Carbamoyl phosphate synthetase (CPS) deficiency
- Ornithine transcarbamoylase (OTC) deficiency
- Citrullinemia type I (Deficiency of argininosuccinic acid synthase)
- Argininosuccinic aciduria (Deficiency of argininosuccinic acid lyase)
- Argininemia (Deficiency of arginase)
All urea cycle defects, except OTC deficiency, are inherited in an
Additional images
-
Urea cycle.
-
Urea cycle colored.
References
- ^ OCLC 901647690.
- ^ ISBN 978-1-4292-8360-1.
- ^ ISBN 978-0-12-410529-4, retrieved 2020-11-10
- ^ PMID 25735860, retrieved 2020-11-10
- ^ ISBN 978-0-323-37101-8, retrieved 2020-11-10
- S2CID 87121092.
- ^ Kaplan Medical USMLE Step 1 Biochemistry and Medical Genetics Lecture Notes 2010, page 261
- ^ PMID 337792.
- PMID 23972786.
- ^ S2CID 13858458.
- ISBN 978-0-7808-1076-1.
- ^ PMID 24145431.
- ISBN 978-0-12-802896-4, retrieved 2020-11-10
External links
- The chemical logic behind the urea cycle
- Basic Neurochemistry - amino acid disorders