Metabolism
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Urea synthesis in the liver, and potentially fatal hyperammonaemia in a child
Key points from this exercise:
The pathway of urea synthesis is cyclic. Arginine is synthesised stepwise form ornithine, and is then hydrolysed to release urea and reform ornithine. This means that adding any of the intermediates of the cycle will increase the rate at which urea is synthesised form ammonium.
One of the nitrogen atoms in urea comes from ammonium, and the other from aspartate.
The ammonium nitrogen comes from either glutamine or adenosine, and is incorporated as carbamoyl phosphate. Carbamoyl phosphate synthetase has an absolute requirement for N-acetylglutamate as an activator.
Aspartate reacts with citrulline to form argininosuccinic acid, which is then cleaved to release fumarate and arginine. Fumarate is metabolised to oxaloacetate via the citric acid cycle, and oxaloacetate is the substrate for transamination to form aspartate. This means that only a catalytic amount of aspartate is required.
Infants who lack argininosuccinase excreted large amounts of argininosuccinic acid in the urine, so depleting their available pool of ornithine to take up ammonium from carbamoyl phosphate. They therefore become hyperammonaemic after a moderately high protein meal. Provision of supplements of arginine provides a linear pathway from ornithine to argininosuccinate for the excretion of ammonium, so relieving the hyperammonaemia.
Urea diffuses form the bloodstream into the intestinal lumen, where it is a substrate for bacterial urease. The ammonium liberated may either be used by bacteria for amino acid and protein synthesis or may be absorbed into the hepatic portal vein and used for synthesis or urea and non-essential amino acids in the liver. Some essential amino acids formed by intestinal bacteria may be absorbed.