Urea cycle:
Urea is synthesized in the liver through the urea cycle. For excretion in the urine it is then secreted into the bloodstream and taken up through the kidneys. The urea cycle was the first cyclic metabolic pathway to be discovered through Kurt Henseleit and Hans Krebs in year of 1932; 5 years before Krebs discovered the citric acid cycle. The whole reaction of the pathway is:
NH4++HCO3-+H2O+3ATP+aspartate →
urea+2ADP+AMP+2Pi+PPi+fumarate
One of the nitrogen atoms of urea comes from ammonia; the other is transferred from the amino acid aspartate, although the carbon atom comes from CO2. Ornithine, an amino acid which is not in the standard group of 20 amino acids and is not found in proteins, is the carrier of these carbon and nitrogen atoms. Five enzymatic reactions are included in the urea cycle that is shown in the figure, the first two of that take place in mitochondria and the other three in the cytosol:
1. Carbamoyl phosphate synthetase, that is technically not a member of the urea cycle, catalyzes activation of ammonia and the condensation (from the oxidative deamination of glutamate through glutamate dehydrogenase;) and CO2 (in the structure of bicarbonate, HCO-) to built carbamoyl phosphate. Hydrolysis of two ATP molecules makes this reaction basically irreversible.
2. The second reaction also occurs in the mitochondria and includes the transfer of the carbamoyl group from carbamoyl phosphate to ornithine through ornithine transcarbamoylase. This reaction built another nonstandard amino acid citrulline that then has to be transported out of the mitochondrion into the cytosol where the remaining reactions of the cycle take place.
3. The citrulline is then condensed with aspartate and the source of the second nitrogen atom in urea, through the enzyme argininosuccinate synthetase to form argininosuccinate. This reaction is driven through the hydrolysis of ATP to PPi and AMP, with subsequent hydrolysis of the pyrophosphate. Therefore both of the high-energy bonds in ATP are ultimately cleaved.
4. Argininosuccinase then erased the carbon skeleton of aspartate from argininosuccinate in the form of fumarate and leaving the nitrogen atom on the other product arginine. As the urea cycle also generates arginine this amino acid is classified as nonessential in ureotelic organisms. The Arginine is the immediate precursor of urea.
5. The urea is then formed from arginine through the action of arginase with the regeneration of ornithine. The ornithine is then sending back into the mitochondrion ready to be combined with another molecule of carbamoyl phosphate.