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Renin Angiotensin Mechanism.

Urea Cycle and its Disorders.

 

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:

  1. Transport of nitrogen to the liver.

  2. Reactions of the urea cycle.

  1. 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.

  1. 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:

  1. Carbamoyl phosphate synthetase I: 

    1. 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.

  2. Ornithine transcarbamylase: 

    1. Combines ornithine and carbamoyl phosphate to form citrulline. Located in mitochondria.

  3. Argininosuccinate synthetase: 

    1. Condenses citrulline with aspartate to form argininosuccinate. This reaction occurs in the cytosol and requires one ATP.

  4. Argininosuccinate lyase: 

    1. Splits argininosuccinate into arginine and fumarate. Occurs in the cytosol.

  5. Arginase: 

    1. 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:

  1. With help of a well labeled diagram describing the Urea Cycle.

  2. Discuss in detail Urea Cycle and the disorders associated with it.
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