Introduction:
Amino acid metabolism produces toxic ammonia which is converted into urea in the liver.
Urea cycle takes place in Mitochondria and cytosol of the liver cells.
A faulty Urea cycle results in toxic levels of ammonia (NH3) within the body, resulting in many symptoms such as lethargy, incoordination, cerebral edema, and asterixis (neurological disorder that causes a person to lose motor control of certain areas of the body).
Location:
Mitochondria and cytosol of the liver cells.
Steps of Urea Cycle:
Transport of nitrogen to the liver.
Reactions of the urea cycle.
Transport of nitrogen to the liver:
Ammonia is very toxic, especially to the CNS.
The concentration of ammonia and ammonium ions in the blood is normally very low. (NH3 + H+ ↔ NH4+)
Ammonia travels to the liver from other tissues, mainly in the form of alanine and glutamine.
It is released from amino acids in the liver by a series of transamination and deamination reactions.
Ammonia is also produced by bacteria in the gut and travels to the liver via the hepatic portal vein.
Reactions of the urea cycle:
Carbamoyl phosphate is synthesized in the first reaction from NH4+, CO2, and two ATP. Inorganic phosphate and two ADP are also produced.
Enzyme: carbamoyl phosphate synthetase I, present in mitochondria.
Ornithine reacts with carbamoyl phosphate to form citrulline. Inorganic phosphate is released.
Enzyme: ornithine transcarbamylase, located in mitochondria. The product, citrulline, is transported to the cytosol in exchange for cytoplasmic ornithine.
Citrulline combines with aspartate to form argininosuccinate in a reaction that is driven by the hydrolysis of ATP to AMP and inorganic pyrophosphate.
Enzyme: Argininosuccinate synthetase
Argininosuccinate is cleaved to form arginine and fumarate.
Enzyme: argininosuccinate lyase. This reaction occurs in the cytosol.
The carbons of fumarate, which are derived from the aspartate added in reaction 3, can be converted to malate.
In the fasting state in the liver, malate can be converted to glucose or to oxaloacetate, which is transaminated to regenerate the aspartate required for reaction 3.
Arginine is cleaved to form urea and regenerate ornithine.
Enzyme: arginase, (located primarily in the liver and is inhibited by ornithine.)
Urea passes into the blood and is excreted by the kidneys.
Ornithine is transported back into the mitochondrion (in exchange for citrulline) where it can be used for another round of the cycle.
Important enzymes in Urea Cycle:
Carbamoyl phosphate synthetase I:
Converts ammonium and bicarbonate into carbamoyl phosphate. This is the rate-limiting step in the urea cycle. This reaction requires two ATP and occurs in the mitochondria.
Ornithine transcarbamylase:
Combines ornithine and carbamoyl phosphate to form citrulline. Located in mitochondria.
Argininosuccinate synthetase:
Condenses citrulline with aspartate to form argininosuccinate. This reaction occurs in the cytosol and requires one ATP.
Argininosuccinate lyase:
Splits argininosuccinate into arginine and fumarate. Occurs in the cytosol.
Arginase:
Cleaves arginine into one molecule of urea and ornithine in the cytosol. The ornithine is then transported back into the mitochondria for entry back into the cycle.
Disorders
A dysfunctional urea cycle leads to urea cycle disorders, which are congenital diseases.
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.
Commonly Asked Questions:
With help of a well labeled diagram describing the Urea Cycle.
Discuss in detail Urea Cycle and the disorders associated with it.