In humans and mammals, almost 80% of the nitrogen excreted is in the form of urea, which is produced through a series of reactions occurring in the cytosol and mitochondrial matrix of liver cells. These reactions are collectively called the urea cycle or the Krebs-Henseleit cycle.
Ammonia is a toxic product of nitrogen metabolism which should be removed from our body. The urea cycle or ornithine cycle converts excess ammonia into urea in the mitochondria of liver cells. The urea forms, then enters the blood stream, is filtered by the kidneys and is ultimately excreted in the urine.
The overall reaction for urea formation from ammonia is as follows:
2 Ammonia + CO2 + 3ATP ---> urea + water + 3 ADP
The urea cycle is a series of five reactions catalyzed by several key enzymes. The first two steps in the cycle take place in the mitochondrial matrix and the rest of the steps take place in the cytosol. Thus the urea cycle spans two cellular compartments of the liver cell.
NH3 + CO2 + 2ATP → carbamoyl phosphate + 2ADP + Pi
Carbamoyl phosphate + ornithine → citrulline + Pi
Citrulline thus formed is released into the cytosol for use in the rest of the steps of the cycle.
Citrulline + ATP + aspartate → argininosuccinate + AMP + PPi
Argininosuccinate → arginine + fumarate
Arginine → urea + ornithine
The overall reaction can be given as follows:
2NH3 + CO2 + 3ATP g urea + 2ADP + AMP + PPi + 2Pi
The main purpose of the urea cycle is to eliminate toxic ammonia from the body. About 10 to 20 g of ammonia is removed from the body of a healthy adult every day. A dysfunctional urea cycle would mean excess amount of ammonia in the body, which can lead to hyperammonemia and related diseases. The deficiency of one or more of the key enzymes catalyzing various reactions in the urea cycle can cause disorders related to the cycle. Defects in the urea cycle can cause vomiting, coma and convulsions in new born babies. This is often misdiagnosed as septicemia and treated with antibiotics in vain. Even 1mm of excess ammonia can cause severe and irreversible damages.
A blood aminogram is routinely used in the diagnosis of urea cycle disorders. The concentration of the nitrogen-carrying amino acids, glutamine and alanine, in plasma is elevated in the case of OTC deficiency. In babies, elevated levels of orotic acid in the urine may be an indicator of OTC deficiency. Increased levels of blood citrulline and argininosuccinate are also seen in cases of citrullinemia.
In older children, these disorders may present in the form of growth failure, psychomotor retardation and behavioral abnormalities. Hence, blood ammonia and urinary orotic acid monitoring and quantitation are crucial in patients with unexplained neurological symptoms.