The urea cycle, also known as the ornithine cycle, is a crucial metabolic pathway in the liver. Its primary function is to convert toxic ammonia, a byproduct of protein metabolism, into urea. Urea is a much less toxic compound that the kidneys can safely excrete through urine. This process is essential for detoxifying ammonia and preventing its harmful accumulation in the body.  Our poster features the key enzymes and steps in the urea cycle, a significant biochemical pathway with relevant health and clinical implications.

The urea cycle consists of five steps, each catalyzed by a specific enzyme. The cycle begins in the mitochondria and continues in the cytosol of hepatocytes. The urea cycle is strictly regulated to ensure efficient detoxification of ammonia. The rate-limiting regulatory enzyme, Carbamoyl Phosphate Synthase 1 (CPS1), is activated by N-acetylglutamate (NAG). NAG is synthesized in response to elevated arginine levels, indicating a high rate of protein metabolism and the need for increased urea production¹.In the mitochondrial matrix, carbamoyl phosphate reacts with ornithine to form citrulline, catalyzed by ornithine transcarbamylase. Citrulline then moves to the cytoplasm, where argininosuccinate synthetase combines it with aspartate to produce argininosuccinate. Argininosuccinate lyase cleaves this into fumarate and arginine. Fumarate can enter cellular respiration and the Krebs cycle to help produce energy. Arginine is hydrolyzed by arginase to yield urea and ornithine, which re-enter the mitochondrial matrix to continue the cycle.

Proper functioning of the urea cycle is essential for maintaining nitrogen balance and preventing the accumulation of toxic ammonia. Genetic disorders can disrupt the urea cycle, leading to hyperammonemia (elevated ammonia levels in the blood) and associated health issues. Urea Cycle Disorders (UCDs) are a group of inherited metabolic disorders caused by mutations in the genes encoding the enzymes of the urea cycle. These disorders can contribute to severe hyperammonaemia, which can cause neurological damage, induce coma, and even death if not treated promptly. Common UCDs include ornithine transcarbamylase deficiency (OTCD), citrullinemia, and argininosuccinic aciduria. Symptoms of UCDs can vary depending on the specific enzyme deficiency and the severity of the disorder. Common symptoms include lethargy, vomiting, seizures, and developmental delays² .

Diagnosis of UCDs typically involves blood tests to measure ammonia levels, perform genetic testing to identify specific mutations, and conduct enzyme assays to assess the activity of urea cycle enzymes. Treatment strategies for UCDs aim to reduce ammonia levels and include dietary management (low-protein diet), medications promoting alternative pathways for ammonia detoxification (e.g., sodium phenylbutyrate), and liver transplantation in severe cases where other treatments are ineffective. The liver plays a central role in the urea cycle, and any impairment in its function can influence the efficiency of ammonia detoxification. Conditions such as liver cirrhosis and hepatitis can disrupt the urea cycle, culminating in hyperammonaemia and hepatic encephalopathy.

The urea cycle is not only central to metabolic health but also a key consideration in clinical research and therapeutic development. Understanding and supporting its function is vital for both scientific progress and patient care.

References

1.    Barmore W, Azad F, Stone WL. Physiology, Urea Cycle. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

2.    Blair NF, Cremer PD, Tchan MC. Urea cycle disorders: a life-threatening yet treatable cause of metabolic encephalopathy in adults. Pract Neurol, Feb;15(1):45-8, 2015.