Urea Cycle: An Introduction

The principal metabolic mechanism involved in the elimination of nitrogenous wastes generated by the breakdown of protein and other nitrogen-containing molecules is called the urea cycle. In the mitochondria of liver cells, the urea cycle converts excess ammonia to urea. Urea is formed, enters the bloodstream, is filtered by the kidneys, and is eventually excreted in the urine. 

The biochemical part of excretion is urea synthesis using the urea cycle, also known as the Ornithine Cycle. It is also known as the Kreb-Henseleit cycle and occurs in the liver. In this article, we will see the regulation and significance of this cycle.

What is Urea Cycle?

  • The urea cycle is a series of biochemical reactions that results in the formation of urea CO(NH2)2 from ammonia (NH3).  

  • Ureotelic animals are amphibians and mammals that use this cycle. 

  • The urea cycle converts highly toxic ammonia to urea, which is then excreted. This cycle was discovered five years before the TCA cycle by Hans Krebs and Kurt Henseleit (Hans Krebs and Kurt Henseleit, 1932). Ratner and Cohen went into greater detail about this cycle later on. 

  • The urea cycle is primarily carried out in the liver and, to a lesser extent, in the kidneys.

  • The urea cycle is irreversible and requires 4 ATP to complete.  

  • Only the liver has all of the enzymes needed to generate urea from ammonia, and this route is only located in periportal hepatocytes.

  • The urea cycle is made up of four different enzyme processes, one mitochondrial and three cytosolic. Carbamoyl phosphate synthetase (CPS), ornithine carbamoyltransferase (OCT), argininosuccinate synthetase, argininosuccinate lyase, and arginase are all implicated. 

  • The urea cycle enzymes ornithine carbamoyltransferase and arginase are also found in the mitochondria, whereas the cytoplasm contains argininosuccinate synthetase and argininosuccinate lyase.

Urea Cycle Biochemistry and Steps Involved 

  1. Carbamoyl Phosphate Synthesis

The mitochondrial carbamoyl phosphate synthetase I (CPS I) catalyses the condensation of NH4+ ions with CO2 to generate carbamoyl phosphate. This process is irreversible and rate-limiting, consuming 2 ATP. CPS I requires N-acetyl glutamate to function. Another enzyme involved in pyrimidine production, carbamoyl phosphate synthetase II (CPS-II), is found in the cytosol. It accepts the amino group from glutamine and does not need N-acetyl glutamate to function.

  1. Citrulline Formation

Citrulline is produced by ornithine transcarbamoylase from carbamoyl phosphate and ornithine. Ornithine is recycled and utilised in the urea cycle. 

  1. Argininosuccinate Synthesis

Argininosuccinate synthase combines with citrulline and aspartate to generate argininosuccinate. This process incorporates the second amino group of urea. This process requires the breakdown of ATP into AMP and pyrophosphate (PPi). The PPi is instantly degraded to inorganic phosphate (Pi).

  1. Argininosuccinate Cleavage

Arginosuccinase cleaves argininosuccinate to produce arginine and fumarate. Urea is a direct precursor of arginine. 

  1. Urea Formation

Arginase is the last enzyme that cleaves arginine to produce urea and ornithine. The regenerated ornithine enters the mitochondria for reuse in the urea cycle. Both CO2 and Mn2+ are activated by arginase. 

Urea Cycle

Urea Cycle

Regulation of Urea Cycle

The first reaction, catalysed by Carbamoyl Phosphate Synthetase I (CPS I), is a rate-limiting or essential step in the production of urea. N-acetyl glutamate (NAG) activates CPS I allosterically. The rate of urea production in the liver is linked to N-acetyl-glutamate concentration. NAG levels rise when arginine levels rise. A protein-rich meal raises the amount of NAG in the liver, resulting in increased urea production.

The mitochondria include carbamoyl phosphate synthetase I and glutamate dehydrogenase. They collaborate in the creation of NH3 and its usage in the synthesis of carbamoyl phosphate. The remaining four urea cycle enzymes are primarily regulated by the concentration of their respective substrates.

Overall Reaction and Energetics

The urea cycle is irreversible and requires 4 ATP to complete. The production of carbamoyl phosphate requires two ATPs. One ATP is converted to AMP and PPi to yield argininosuccinate, which is equivalent to two ATP. As a result, 4 ATP is actually consumed.

NH4+ + CO2 + Aspartate + 3ATP → Urea+ Fumarate + 2ADP + 2 Pi + AMP + PPi

Significance of Urea Cycle

  • The urea cycle, also known as the “Ammonia Detox Cycle”, is the process by which ammonia is removed from the body.

  • Toxic ammonia is transformed into harmless urea. It eliminates two waste products: ammonia and CO2.

  • It produces arginine, a semi-essential amino acid. It helps to regulate blood pH, which is determined by the dissolved CO2 ratio, e.g. H2CO3 to HCO3.

  • Ornithine is a precursor of polyamines such as spermidine and spermine.

  • Ammonia is a byproduct of protein metabolism that is hazardous to the human body, particularly the central nervous system. As a result, ammonia is transformed into urea, a harmless water-soluble molecule that is excreted through urine.

Importance of Urea Cycle

  • NH4+ is a byproduct of amino acid degradation.

  • Cells require NH4+ for the production of nitrogen-containing molecules.

  • Excess NH4+ is extremely harmful to our body. So, the excess NH4+ is transformed into urea and eliminated via the urea cycle. The urea cycle accounts for 80% of the nitrogen excreted.

  • TCA cycle intermediates are recycled.

  • Amino acids and keto acids are recycled.

Urea Cycle Disorder

The table describes metabolic disorders related to each of the five urea cycle enzymes. All of the disorders always result in an increase in blood ammonia (hyperammonemia), which leads to toxicity. Another urea cycle byproducts accumulate as well, depending on the individual enzyme deficiency. Clinical signs of urea cycle enzyme deficiencies include vomiting, drowsiness, irritability, stiffness, and mental retardation.


Enzyme Involved 

Hyperammonemia type I

Carbamoyl phosphate synthetase I

Hyperammonemia type II

Ornithine transcarbamylase


Argininosuccinate synthase

Argininosuccinic aciduria





Urea cycle is a series of metabolic reactions that occur in the liver to convert ammonia to urea. The urea cycle is made up of six enzymes that rid the body of nitrogen produced during amino acid metabolism. They break it down into urea, which is excreted in the urine. This article talks about the importance and regulation of the Urea Cycle. There are different disorders also related to the improper functioning of the enzymes of the urea cycle.

Want to read offline? download full PDF here
Download full PDF
Is this page helpful?

FAQs on Urea Cycle

1. What are ureotelism and ureotelic animals?

Terrestrial adaptation required the synthesis of less harmful nitrogenous wastes like urea and uric acid in order to conserve water. Since urea is 100,000 times less hazardous than ammonia, it may be tolerated at considerably higher concentrations. Ureotelism is the process through which urea is excreted. Ammonia generated by metabolism is converted to urea in these animals' livers and released into the bloodstream, where it is filtered and expelled by the kidneys. Ureotelic animals are mammals, numerous terrestrial amphibians, and marine fishes that mostly excrete urea.

2. What happens when the urea cycle goes wrong?

If the urea cycle fails, the level of ammonia in the blood rises, resulting in hyperammonemia. Ammonia has the ability to pass through the blood-brain barrier. If a child has a urea cycle disorder, their liver is unable to produce one of the enzymes required by the cycle. When their bodies are unable to remove nitrogen, ammonia forms and accumulates in their blood. It's toxic and can damage their brains or put them in a coma. If not treated promptly, it can be fatal.

3. Which enzyme is the pacemaker for the urea cycle?

Since it is the rate-limiting step, CPS I is essentially the urea cycle's pacemaker enzyme. CPS catalyses the synthesis of carbamoyl phosphate (CP) from ATP and bicarbonate, depending on the type of enzyme, using glutamine or ammonia as a nitrogen source. Thus, eukaryotes have three CPS isoforms that are used to generate CP for use in various metabolic pathways. Prokaryotes, on the other hand, have a single CPS, classified as Type II, for which glutamine is the sole nitrogen source.

Competitive Exams after 12th Science