In the urea cycle, nitrogen-containing metabolic end products are converted to urea. This biochemical process takes place in the liver. Urea is then excreted by the kidneys.
What is the urea cycle?
In the urea cycle, metabolic end products containing nitrogen are converted to urea. Proteins, or proteins, are made up of many amino acids. These in turn contain at least one nitrogen molecule in the form of an amino group (-NH2). When the amino acids and their nitrogen molecules are broken down, toxic ammonia (NH3) is formed. In the blood, the ammonia is dissolved in the form of so-called ammonium ions (NH4+). Even in this dissolved form, the substance can have a toxic effect. In the liver, urea is formed by binding the ammonium ions. This renders the ions harmless. The urea formed is excreted through the kidneys. Humans are dependent on the urea cycle. Most aquatic animals can immediately release the resulting ammonia into the water through their body fluids by osmosis. In birds and lizards, the more harmless uric acid is produced instead of urea. This is also excreted through the urine, but unlike urea, it can remain in the body longer without causing damage.
Function and task
The urea cycle, also called the ornithine cycle, begins in the mitochondria. Mitochondria are also known as the power plants of the cell because this is where the very high-energy molecule ATP is produced. Within the matrix of the mitochondria, carbamoyl phosphate is formed from free ammonia and carbon dioxide by the enzyme carbamoyl phosphate synthetase 1. This reaction leaves a phosphate residue. This is needed in the next step. Here, ornithine, an amino acid present in the mitochondrial matrix, reacts with the carbamoyl phosphate formed in the first step. In this process, the carbamoyl phosphate transfers its carbamoyl group to the ornithine. Citrulline and phosphate are formed. The catalyst of this chemical reaction is the enzyme ornithine transcarbamylase. For the process to continue, the citrulline formed must be transported from the mitochondria into the cell fluid of the liver cells (hepatocytes). This is done with the help of the ornithine-citrulline transporter. In the cytoplasm of hepatocytes, the amino group aspartate also becomes part of the urea cycle. The carbonyl group of citrulline reacts with aspartate. This produces argininosuccinate by the catalyzing enzyme argininosuccinate synthetase. This is cleaved by another catalyzing enzyme, argininosuccinase, into free furamate and free arginine. The free furamate is regenerated to aspartate. The arginine is in turn cleaved by the enzyme arginase. This produces urea and ornithine. The ornithine is transported back to the mitochondrion where it serves as a carrier molecule in the formation of citrulline. The urea is excreted by the kidney as a water-soluble molecule. Thus, without the urea cycle, the metabolic toxin ammonia cannot be disposed of. Urea thus serves to detoxify the body. If it is disturbed, severe neurological symptoms can occur. A healthy liver is particularly important for a functioning urea cycle, as this is where the majority of urea formation takes place. Only a small and negligible part of urea formation takes place in the kidney. However, since the kidney excretes the urea, the urea content in the blood is used to detect and monitor the progress of renal insufficiency. Blood urea levels also play a role in dialysis monitoring or in determining a cause of coma.
Diseases and complaints
A total of six disorders of urea metabolism are known. These are always the result of a disorder of an enzyme involved. Thus, there is usually a deficiency of carbamoyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase , argininosuccinate lyase, arginase, or N-acetyl glutamate synthetase in disorders of urea metabolism. Deficiency of any of these enzymes always results in pathologically high accumulation of ammonia in tissues and blood. An elevated blood ammonia level is also referred to as hyperammonemia. Hyperammonemia can also be caused by dysfunction in the liver. In particular, advanced liver diseases such as chronic hepatitis or liver cirrhosis impair the urea cycle due to the death of liver cells.The consequences of a severe disturbance in the urea cycle are primarily damage to the central nervous system. This condition is also referred to as hepatic encephalopathy. If the urea cycle is disturbed, too much toxic ammonia remains in the blood. The cytotoxin primarily attacks the cells of the nervous system. These swell as a result of the poisoning. This increases the intracranial pressure and eventually leads to cerebral edema. The symptoms can be divided into four stages. In the first stage, there are only mild changes such as concentration disorders or mood swings. In some cases, however, those affected already have problems solving simple arithmetic problems at this stage. In the second stage, there is increased sleepiness. The temporal orientation is limited. This is followed by speech and consciousness disorders. Patients suffer from abnormal sleepiness, but are still responsive and can be awakened. The most severe form of hepatic encephalopathy is hepatic coma, also called coma hepaticum. This stage is characterized by complete unconsciousness and the complete absence of reflexes. Hepatic coma is often fatal. The manifestation of symptoms in urea cycle disorders is favored by some factors. For example, infections can lead to increased cellular decay and thus to an increased accumulation of amino acids. Increased dietary protein intake can also overload the already disturbed urea cycle. The therapy of disorders in the urea cycle is carried out medicinally with phenyl acetate and benzoate. Both react together with glutamine and glycine to form phenacetylglutamine and hippuric acid. Like urea, these can remove nitrogen and are also excreted in the urine.
