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Urea Cycle and Its Disorders

Urea cycle, Defects in the urea cycle and their consequences, The urea cycle is affected by a variety of disorders, NAGS deficiency, CPS1 deficiency

Urea cycle

Toxic ammonia is converted into urea in the liver. The liver's mitochondria and cytoplasm are the only places where this energy-dependent process takes place. A failed metabolic process results in toxic levels of ammonia (NH3) within the body, resulting in symptoms such as lethargy, incoordination, cerebral edema, and asterixis.

Cellular level

Hepatocytes form the first stage in the urea cycle in their mitochondria and end it in their cytoplasm.

Step 1

Secondly, the enzyme carbamoyl phosphate synthetase I (CPS I) is responsible for converting CO and ammonia into carbamoyl phosphate. The first amine group in urea is derived from ammonia. In this step, N-acetyl-glutamate (NAG) is required as an obligate activator. As glutamate + acetyl-CoA is converted into NAG through NAG synthase, arginine upregulates this enzyme. NH and HCO+ may be used in some sources, but these are equivalent to CO+ HO + NH.

CO+ NH+ 2ATP produces carbamoyl phosphate +2ADP + P

Synthesis of NAG: glutamate + acetyl-CoA NAG

Step 2

Ornithine transcarbamoylase (OTC) combines carbamoyl phosphonate and ornithine to form citrulline. Ornithine translocase transports citrulline into the cytoplasm from mitochondria in hepatocytes.

Ornithine citrulline + carbamoyl phosphate

The mitochondria contain citrulline, while the cytoplasm contains citrulline

Step 3

Aspartate forms argininosuccinate when citrulline is reacted with it. Argininosuccinate synthetase is responsible for carrying out this reaction, for which ATP is required. The second amine group of urea is derived from aspartate. Using aspartate transaminase, which requires vitamin B, aspartate is produced by transamination of oxaloacetate and glutamate.

Asparte + ATP argininosuccinate + citrulline

Alpha-ketoglurate + Oxaloacetate + glutamate aspartate

Step 4

Through argininosuccinate lyase, argininosuccinate is converted into arginine. As well as releasing fumarate, this reaction causes mitochondria to generate NADH in the TCA cycle and catabolize tyrosine.

Fumarate + argininosuccinate anarginine

Step 5

Urea and ornithine are formed when arginine undergoes hydrolysis by arginase. Read through step 2. There is a role for ornithine regeneration in step 2 as well.

HO urea + ornithine + arginine

Toxic ammonia is converted into urea by the urea cycle in the body. Whether it's from protein catabolism, deamination, or prolonged starvation, ammonia is produced through protein catabolism. In addition, gut bacteria also produce ammonia. Muscles and peripheral tissues produce glutamine from glutamate, which is an amino acid that accepts free ammonia. Muscles and peripheral tissues export glutamine, which is then used by the liver. Glutamine is broken down by glutaminase into glutamate and ammonia. Through glutamate dehydrogenase, glutamate yields additional urea. Hepatocyte mitochondria incorporate ammonia into urea, which is eventually metabolized to form urea. The urine is then excreted in the urine after leaving the hepatocyte cytoplasm.


A dysfunctional urea cycle leads to urea cycle disorders, which are congenital diseases. These disorders have been extensively studied from a genetic and biochemical perspective. An enzyme deficiency alters the biochemical reactions involved in converting ammonia to urea in the urea cycle, which is subsequently removed via urine. Disorders of the urea cycle are caused by inborn metabolism errors that can lead to brain damage and death in newborns.

Defects in the urea cycle and their consequences

Symptoms of hyperammonemia occur when the urea cycle enzyme is absent or deficient, which results in an accumulation of ammonia in the body and an elevated blood level of ammonia. When ammonia enters the bloodstream, it damages the brain irreversibly, causing comas and death. Without treatment, children develop physically and mentally slow.

The urea cycle is affected by a variety of disorders

There are eight disorders of the urea cycle caused by deficiencies of the enzymes and transporter proteins that are involved in the cycle.

N-acetyl glutamate synthase (NAGS) deficiency - CPS1 (carbagamoylphosphate synthetase I) is the first enzyme in the urea cycle that needs NAGS to work. Due to the inactivation of CPS1 when NAGS is absent, hyperammonemia symptoms are similar to those associated with CPS1 deficiency. By using carglumic acid, hyperammonemia can be fully treated as a result of the only urea cycle defect.

Carbamoylphosphate synthetase I (CPS1) deficiency - Hyperammonemia in newborns occurs when CPS1 completely fails to function. Even after treatment and recovery, they are chronically at risk of hyperammonemia due to this very serious urea cycle disorder. When a person is exposed to stress or infection, they may experience symptoms due to partial or mild CPS1 deficiency.

Ornithine transcarbamylase (OTC) deficiency - OTC deficiency is as severe as CPS1 and is mostly seen in males whose X chromosome has only one gene encoding OTC. OTC deficiency is less common among females due to the presence of two X chromosomes and the likelihood of having one functional OTC gene. Women only suffer from OTC deficiency and develop hyperammonemia in about 15% of cases, requiring chronic medical treatment.

Argininosuccinate synthase 1 (ASS1) deficiency or citrullinemia deficiency type I - Affected individuals suffer from severe hyperammonemia due to this defect. In addition, blood levels of citrulline are abnormally high in affected individuals.

Citrin deficiency or citrullinemia deficiency type II - Aspartate is transported into the urea cycle by Citrin, a transporter protein. Hyperammonemia occurs when this protein is deficient, causing seizures and comas. The mutations in Citrin are more common in populations of Asian descent.

Argininosuccinic lyase (ASL) deficiency - Hyperammonemia occurs rapidly in newborns with this condition. Chronic liver enlargement and increased transaminase levels are related to this condition. Fibrosis may develop as a result of enlarged hepatocytes.

Arginase (ARG) deficiency - Some patients experience progressive spasticity and slow growth as a result of this defect, which does not cause rapid-onset hyperammonemia.Ornithine translocase deficiency - Within the urea cycle, ornithine and citrulline molecules are transported by the ornithine translocase. Ammonia builds up when the cycle is stalled by a lack of this protein. Coma, hyperammonemia reactions, and vomiting are common symptoms.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of pharmaguideline.com, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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