Biochemistry: Deamination and Urea Cycle

Deamination of Histidine

• Histidine is deaminated by histidinase (histidine ammonia lyase) to yield ammonia and urocanate.

Other Reactions that Produce Ammonia

• Asparaginase and glutaminase hydrolyze the side-chain amides of asparagine and glutamine respectively to yield aspartate and glutamate.
• Serine dehydratase catalyzes the pyridoxal-5-phosphate dependent dehydration of serine and threonine to yield pyruvate and α-ketobutyrate, and ammonia.
• The purine nucleotide cycle operates in muscle, releasing ammonia when AMP is converted to IMP.
• L and D amino oxidase reactions, primarily occurring in the kidney, racemize D-amino acids to L-amino acids.

The Urea Cycle

• The urea cycle is the primary pathway for detoxifying ammonia in the body.
• Two nitrogen atoms in urea are derived from ammonia and aspartate, while the carbon atom comes from bicarbonate.
• Some reactions of the urea cycle occur in the mitochondria, others in the cytosol.
• Glutamate dehydrogenase, the enzyme that feeds ammonia into the urea cycle, is located in the mitochondria.
• Ammonia, released from glutamate dehydrogenase, reacts with bicarbonate to form carbamoyl phosphate.
• This reaction is catalyzed by carbamoyl phosphate synthetase I (CPS1).
• CPS1 differs from CPSII, the cytosolic enzyme responsible for carbamoyl phosphate production for pyrimidine biosynthesis.
• CPS1 is activated by N-acetyl glutamate (NAG), synthesized when there is extensive amino acid deamination.
• Ornithine serves as the 'carrier' molecule in the urea cycle, reacting with carbamoyl phosphate to form citrulline.
• Citrulline leaves the mitochondria and moves into the cytosol for further reactions in the urea cycle.
• The second nitrogen atom in urea is acquired from aspartate in a reaction catalyzed by argininosuccinate synthetase.
• Argininosuccinate lyase removes fumarate from argininosuccinate, resulting in arginine.
• Arginase hydrolyzes arginine to release urea and regenerate ornithine.
• The urea cycle is linked to glycolysis and the TCA cycle through pyruvate, oxaloacetate, α-ketoglutarate, and fumarate.

Control of the Urea Cycle

• The urea cycle is regulated through substrate availability, allosteric regulation of CPS1 by NAG, and induction of urea cycle enzymes.
• Induction of urea cycle enzymes occurs in response to high protein diets, prolonged fasting, or starvation, when protein breakdown is increased.

Defects of the Urea Cycle

• Defects in any of the urea cycle enzymes can lead to mental retardation, seizures, coma, and early death.
• Deficiencies in CPS1 and ornithine transcarbamoylase are particularly dangerous, often resulting in high ammonia levels.

Removal and Disposal of Amino Acid Nitrogen

• Deamination of amino acids results in the production of ammonia.
• Ammonia is toxic and is converted to urea in the liver for detoxification.
• Urea is excreted in urine.
• Ammonia produced in tissues other than the liver is transported to the liver mainly as glutamine and alanine.
• Liver extracts amino acids from the blood and deaminates them, producing ammonia for detoxification.
• The primary route of amino acid deamination involves the transfer of amino groups from amino acids to α-ketoglutarate, forming glutamate (transamination).
• Glutamate dehydrogenase removes the amino group from glutamate as ammonia through oxidative deamination.
• Glutamate dehydrogenase is the main amino acid dehydrogenase active in the body.