The Urea Cycle Step by Step

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Elimination of ammonia

Ammonia can be produced by the break-down of amino acids, or by the gut bacteria in humans. If the level of ammonia in the blood becomes too high, then it becomes toxic to the brain.

The urea cycle removes ammonia from the blood and makes urea, which is eventually excreted as urine. This cycle is carried out by the cells of the liver, and, as the name suggests, the last step of the process feeds into an earlier step of the cycle.

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Summary of the urea cycle

Ammonia is formed by the breakdown of amino acids/gut bacteria.

The mitochondrial stage:

  • Carbamoyl phosphate is formed from ammonia and bicarbonate, by carbamoyl phosphate synthetase (CPS).
  • Ornithine transcarbamoylase (OTC) condenses carbamoyl phosphate and ornithine to form citrulline.
  • Citrulline is then transported to the cytosol by SLC25A15.

The cytosolic stage:

  • Argininosuccinate synthetase (AS) condenses citrulline and aspartate to form argininosuccinate.
  • Argininosuccinate is broken down into arginine and fumarate by argininosuccinate lyase (AL).
  • Arginine is broken down into urea and ornithine by arginase.
  • Ornithine translocase transports ornithine into the mitochondria.

The mitochondrial stage

The first two steps of the urea cycle occur in the mitochondria of the cell. First, the enzyme CPS takes ammonia and bicarbonate and forms carbamoyl phosphate with the use of adenosine triphosphate (ATP). This is the step in the cycle that determines how fast the cycle progresses. N-acetylglucosamine is also required for CPS to function, and functions as a regulator for the formation of urea.

OTC then condenses carbamoyl phosphate and ornithine, which forms citrulline. This citrulline is then moved out of the mitochondria into the cytosol of the cell by the transporter SLC25A15.

The cytosolic stage

AS takes the citrulline formed in the mitochondrial stage and condenses it with aspartate to form argininosuccinate. This occurs by the formation of an intermediate, citrulline-AMP.

Argininosuccinate is then broken into arginine and fumarate by AL. Fumarate is then incorporated into another metabolic cycle, the tricarboxylic acid (TCA) cycle. The TCA cycle, which is also known as the citric acid cycle or the Krebs cycle, can then reform aspartate, which is used by AS.

Arginine is then further broken down into urea and ornithine by arginase. Arginine can also be acquired from the diet, and this can also be taken in by the liver cells and broken down into urea and ornithine by arginase.

The ornithine is then transported into the mitochondria by ornithine translocase. There, it is used by OTC again to form citrulline. The citrulline is then processed to form urea and ornithine again, and the cycle continues. During the cycle, urea is the only new product which is formed, while all other molecules used in the cycle are recycled.

What happens when the urea cycle goes wrong?

If there is a problem with the urea cycle, then the level of ammonia in the blood will rise, causing hyperammonemia. Ammonia is able to cross the barrier between the bloodstream and the brain. Once it enters the brain, it can stop the TCA cycle by depleting one of the metabolites, α-ketoglutarate. This means that these brain cells cannot make energy, ultimately leading to their death. This eventually will lead to neurological problems, which can be as severe as irreversible brain damage.

Problems can arise as a redsult of damage to the liver (cirrhosis) or by an inherited defect in one of the above enzymes. In both cases, the level of ammonia rises with the potential consequences previously detailed.

Inherited urea cycle defects are part of “inborn errors in metabolism”, and are known as “urea cycle disorders.” Symptoms usually present in newborns around 24-48 hours after birth. The most severe symptoms are seen in newborns with a defect in CPS.

Treatment for hyperammonemia consists of removing protein from the diet, removing the excess ammonia and supplementing with molecules of the urea cycle which are missing. Also, sodium benzoate and sodium acetate can be used to form ammonia-containing compounds that can be excreted through feces.

The sugar lactulose has been shown to reduce the production of ammonia by the gut bacteria, as well as promote the excretion of ammonia through the feces. Alternatively, antibiotics can be used to eliminate the ammonia-forming gut bacteria.

Urea Cycle Disorders


Further Reading

Last Updated: Apr 25, 2021

Dr. Maho Yokoyama

Written by

Dr. Maho Yokoyama

Dr. Maho Yokoyama is a researcher and science writer. She was awarded her Ph.D. from the University of Bath, UK, following a thesis in the field of Microbiology, where she applied functional genomics to Staphylococcus aureus . During her doctoral studies, Maho collaborated with other academics on several papers and even published some of her own work in peer-reviewed scientific journals. She also presented her work at academic conferences around the world.


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  1. Bronson Stone Bronson Stone Australia says:

    Thank you Dr Maho, your explanation is one of the best I have seen, very easy to understand.
    Would you please explain a little further, as I have some confusion in regard to Citrulline supplementation helping eliminate ammonia by it's support of the Urea cycle.

    You said:
    Carbamoyl phosphate is formed from ammonia and bicarbonate, by carbamoyl phosphate synthetase (CPS).
    Ornithine transcarbamoylase (OTC) condenses carbamoyl phosphate and ornithine to form citrulline.

    This suggests to me that citrulline is a product formed from ammonia, therefore how does supplemental citrulline which must also be a product of ammonia reduce the body burden of ammonia? (I am asking this because I have read in numerous articles that supplemental citrulline will assist in eliminating ammonia. But they didn't explain how it is possible.)

    Thank you

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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