12. Urea cycle

Last updated on January 11, 2020 at 14:23


  • Ammonia, NH3 (and therefore ammonium, NH4+) is toxic to the brain, so it should be excreted
  • The first two reactions of the urea cycle are in the mitochondria, the other three in the cytosol
  • The main product of the urea cycle is urea, but fumarate is also produced
  • The cycle is regulated by N-acetylglutamate, which stimulates the first reaction in the cycle
  • The urea cycle is connected to the glycolysis by fumarate and aspartate

The cycle

The cycle begins with the synthesis of carbamoyl phosphate by carbamoyl phosphate synthase 1. Carbamoyl phosphate is then attached to ornithine to yield citrulline. Citrulline + aspartate yields argininosuccinate. The enzyme argininosuccinase cleaves argininosuccinate into fumarate and arginine. Arginine loses one molecule of urea while becoming ornithine, which can start the cycle anew.

The cycle is energetically expensive. It consumes 4 ATP, but also produces 1 fumarate. This fumarate gives 1 NADH (=2.5 ATP) in the citric acid cycle, so the net ATP use of the urea cycle becomes 4 – 2.5 = 1.5 ATP.

Where are the sources of ammonia?

  • Amino acid degredation
  • Degredation of pyrimidine bases
  • Produced by intestinal bacteria

The aspartate-argininosuccinate shunt

As outlined above, one fumarate molecule is produced in the urea cycle. However, the urea cycle occurs in the cytosol, while the citric acid cycle occurs in the mitochondria. This fumarate needs to be transported into the mitochondria to be useful. This is overcome by cytosolic fumarase, which converts the fumarate into malate. This malate can be transported into the mitochondria, where it enters the citric acid cycle to be converted into oxaloacetate, which yields 1 NADH (= 2.5 ATP). This oxaloacetate can be transaminated with glutamate to yield α-ketoglutarate and aspartate. This aspartate then goes into the urea cycle. This cycle is called the aspartate-argininosuccinate shunt.

A figure showing the urea cycle and how it connects with the citric acid cycle through the aspartate-argininosuccinate shunt.

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11. Amino acid metabolism; the fate of the amino group

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13. Amino acid metabolism; the fate of the carbon skeleton

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