Urea Cycle Notes

Urea cycle In higher terrestrial animals, ammonia is converted into less toxic urea. Formation of urea occurs inside the liver, which involves two processes: Release of ammonia by deamination of amino acids. Synthesis of urea by the ornithine cycle. 1) Release of Ammonia: The amino group (-NH2) of the amino acids is removed by a process called deamination so that it is converted to α-keto acid. The process of deamination occurs in two ways under the influence of enzymes: Oxidative Deamination: It requires several steps and enzymes. First, the amino acid is dehydrogenated by flavoprotein or the oxidase, forming α-iminio acid. By adding water, it decomposes into corresponding keto acid, releasing NH3. Amino acid + H2O → α-iminio acid + H2O → Keto acid + NH3 (Chemical reaction diagram) 2) Hydrolytic deamination: Some sulfur-containing amino acids such as glutamic acids and aspartate acids are deaminated by hydrolytic enzymes. Glutamic acid + NAD + H₂O → Glutamate dehydrogenase → α-keto-glutaric acid + NADH₂ + NH₃ (Chemical structure of Glutamic acid) II) Synthesis of Urea: The synthesis of urea occurs in the liver. It involves a cyclic chain of chemical reactions called the Krebs-Henseleit cycle, first described by Krebs and Henseleit. During this process, ammonia, CO₂, ATP, and aspartic acids are consumed. This cycle is also called the urea cycle or ornithine cycle. It occurs in the following steps: Steps: (Synthesis of carbamyl phosphate): Molecules of NH₃ with CO₂ and H₂O are condensed to carbamyl phosphate in the presence of 2 molecules of ATP and Mg²⁺ and the enzyme carbamyl phosphate synthetase. NH₃ + CO₂ + H₂O + 2 ATP → Synthetase → Carbamyl phosphate + 2 ADP Step-II (Synthesis of citrulline): The carbamyl phosphate reacts with ornithine forming citrulline in the presence of enzyme ornithine carbamyl transferase. This step is found in the mitochondria of liver cells, and all the rest of the steps occur in the cytoplasm. Carbamyl phosphate + ornithine → Citrulline Step-III (Synthesis of Argininosuccinic Acid): Through aspartic acid, the second molecule of NH₃ is introduced. It joins with citrulline in the presence of ATP, Mg²⁺, and the enzyme argininosuccinate synthetase to form argininosuccinic acid. Citrulline + NH₃ + ATP → Argininosuccinic acid Step-IV (Formation of Arginine and Fumaric Acid): Argininosuccinic acid breaks up into arginine and fumaric acid. This reaction is catalyzed by the enzyme argininosuccinase. Argininosuccinic acid → Arginine + Fumaric acid Fumaric acid is formed and can enter into the Krebs cycle. Step-V (Formation of Ornithine and Urea): Arginine is hydrolyzed in the presence of enzyme arginase into urea and ornithine. Ketogenesis: The formation of ketone bodies is called ketogenesis. Ketone bodies are normally produced in the mitochondria of liver cells and continuously released into the blood. In some metabolic conditions, such as prolonged starvation and diabetes mellitus, oxidation of fatty acids is accelerated, producing large amounts of acetyl-CoA. The acetyl-CoA cannot be fully utilized through the TCA cycle, and some acetyl-CoA are converted to ketone bodies. Steps of Ketogenesis: During ketogenesis, acetoacetate is the ketone body that is synthesized first, from which other ketone bodies are formed. It involves the following steps: Two molecules of acetyl-CoA condense to form acetoacetyl-CoA by thiolase. Acetyl-CoA + Acetyl-CoA → Acetoacetyl-CoA + CoASH Acetoacetyl-CoA further condenses with another molecule of acetyl-CoA to form hydroxy-methylglutaryl-CoA by synthase. Acetoacetyl-CoA + Acetyl-CoA → Hydroxy-methylglutaryl-CoA + CoASH Splitting of Hydroxy-methylglutaryl-CoA produces acetoacetate and acetyl-CoA by the enzyme lyase. Hydroxy-methylglutaryl-CoA → Lyase → Acetoacetate + Acetyl-CoA Clinical Significance of Ketogenesis: Some clinical disorders due to ketone are as follows: Ketonemia: It is the increased concentration of ketone bodies in blood than normal. Ketonuria: Increased excretion of ketone bodies in the urine. Ketosis: It is the increased synthesis of ketone bodies leading to ketonemia. Acidosis: Accumulation of excess ketone bodies in blood causing lowering of blood pH.