Urea Cycle Definition

• The metabolic process known as the urea cycle converts nitrogen into urea for excretion from the body.
• Nitrogenous excretory materials are mostly removed from the body through urine.
• The kidneys easily eliminate urea, which is benign, highly soluble, and replaces ammonia, which is very harmful to humans.
• A healthy adult excretes around 30 g of urea each day, that accounts for approximately 90 percent of the nitrogenous excretory materials.
• The urea cycle uses aspartate nitrogen, NH4+, CO2, and oxygen to produce urea.
• The liver is where the cycle mostly happens.

Location of the Urea Cycle

Hepatocytes’ cytosol as well as mitochondria

• Substrates include aspartate, CO2, NH3 (which is produced when glutamate is oxidatively deaminated), and three ATP.
• products: urea, fumarate, and water.

Steps in the Urea Cycle

1. Transport of nitrogen to the liver

• Ammonia is extremely toxic throughout the body, particularly the central nervous system.
• Normal levels of ammonia as well as ammonium ions in the blood are quite low.

(NH3 + H+ ↔ NH4+)

• The major forms of ammonia that are transported from other tissues to the liver are alanine and glutamine.
• Through a sequence of transamination and deamination events in the liver, it is released from amino acids.
• Additionally, microorganisms in the stomach create ammonia, which travels via the hepatic portal vein to the liver.

2. Reactions of the urea cycle

Aspartate and NH4+ supply the nitrogen when CO2 supplies the carbon in the production of urea. The cycle regenerates ornithine, which is used as a carrier.

• From NH4+ and CO2, with two ATP, carbamoyl phosphate is produced in the first step. Additionally, two ADP and inorganic phosphate are generated.
• The mitochondrial enzyme carbamoyl phosphate synthetase I is activated by N-acetylglutamate.
• Combining ornithine with carbamoyl phosphate produces citrulline. Inorganic phosphorus is released.
• The enzyme ornithine transcarbamoylase is found in mitochondria. Citrulline is transported to the cytosol in replacement of cytoplasmic ornithine.
• In a process fueled by the hydrolysis of ATP to AMP and inorganic pyrophosphate, citrulline mixes with aspartate to create argininosuccinate.
• Argininosuccinate synthetase is an enzyme.
• Arginine and fumarate are produced via the cleavage of argininosuccinate.
• Argininosuccinate lyase is the enzyme. In the cytosol, this process takes place.
• Malate may be created from the carbons in fumarate, resulting from the addition of aspartate in reaction 3.
• Malate may be metabolised by the liver during a fast to either glucose or oxaloacetate. It is subsequently transaminated into the aspartate required for step 3.
• For the production of urea and regeneration of ornithine, arginine is broken down.
• Ornithine inhibits the enzyme arginase, which is mostly present in the liver.
• Urea is eliminated by the kidneys when it reaches the circulation.
• Citrulline is used to carry ornithine back into the mitochondrion, where it may be used for a subsequent cycle.
• Additional ornithine is produced by the cell from glucose using glutamate when it is needed.
• Adults do not need the amino acid arginine. Through the use of ornithine as well as the initial four stages of the urea cycle, it is produced from glucose.

Important enzymes in the urea cycle

• Carbamoyl phosphate synthetase I:The enzyme carbamoyl phosphate synthetase I produce carbamoyl phosphate from ammonium and bicarbonate. The urea cycle’s rate-limiting phase is this one. The mitochondria are where this process takes place, and it needs two ATP.
• Ornithine transcarbamoylase:Citrulline is produced by ornithine transcarbamoylase, which combines ornithine with carbamoyl phosphate, in the mitochondria.
• Argininosuccinate synthetase: Citrulline and aspartate are combined by the enzyme argininosuccinate synthetase to create arginosuccinate. One ATP is needed for this cytosolic reaction.
• Argininosuccinate lyase:The enzyme argininosuccinate lyase breaks down argininosuccinate into fumarate and arginine, takes place in the cytosol.
• Arginase:Arginase converts a single molecule of urea and a molecule of ornithine from cytosolic arginine. The ornithine is then sent back to the mitochondria for re-entry into the cycle after that.

Regulation of the Urea Cycle

• The rate-limiting step of the cycle is catalysed by carbamoyl phosphate synthetase I, which is stimulated by N-acetylglutamate.
• A high-protein diet for at least four days stimulates the urea cycle enzymes, despite the liver’s strong inherent capacity for urea generation.

The Purpose of the Urea Cycle

• The urea cycle converts ammonia into urea, which is subsequently eliminated by the kidneys, allowing for the excretion of NH4+.

Related Diseases of the Urea Cycle

• When one or more of the urea cycle enzymes are deficient, NH4+ is not removed from the body enough, leading to hyperammonemia.
• The effects of ammonia poisoning on the CNS include mental impairment, seizures, coma, and death.

References

• Smith, C. M., Marks, A. D., Lieberman, M. A., Marks, D. B., & Marks, D. B. (2005). Marks’ basic medical biochemistry: A clinical approach. Philadelphia: Lippincott Williams & Wilkins.
• Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
• John W. Pelley, Edward F. Goljan (2011). Biochemistry. Third edition. Philadelphia: USA.
• Madigan, M. T., Martinko, J. M., Bender, K. S., Buckley, D. H., & Stahl, D. A. (2015). Brock biology of microorganisms (Fourteenth edition.). Boston: Pearson.
• Rodwell, V. W., Botham, K. M., Kennelly, P. J., Weil, P. A., & Bender, D. A. (2015). Harper’s illustrated biochemistry (30th ed.). New York, N.Y.: McGraw-Hill Education LLC.