Amino Acid Oxidation and Urea Cycle

Amino Acid Oxidation and the Urea Cycle

• Proteins are nitrogen-containing macromolecules made of L-α-amino acids.
• Dietary protein is the main source of amino acids.
• Amino acid catabolism is part of whole-body catabolism, contributing significantly to energy production.
• Carnivores rely heavily on amino acid oxidation for energy.
• Herbivores utilize amino acids to a lesser extent.
• Microorganisms also utilize amino acids as a source of fuel.
• Photosynthetic plants rarely utilize amino acids for energy.
• In animals, amino acid oxidation occurs in three different metabolic conditions: during normal protein synthesis, a protein-rich diet, and starvation/diabetes.
• Excess amino acids cannot be stored and are either excreted or used as fuel.
• The alpha-amino group of the amino acids is removed, and the carbon skeleton is converted into a major metabolic intermediate.
• Most amino groups from surplus amino acids are converted into urea.
• The major site of amino acid degradation in mammals is the liver.

Dietary Protein Degradation

• Gastrin stimulates HCl secretion to begin protein denaturation.
• Pepsinogen is converted to active pepsin.
• Pepsin cleaves proteins.
• Enzymes in the small intestine neutralize the acid and function in protein degradation.
• Secretin inhibits gastric acid secretion, signals the pancreas, and stimulates the gall bladder to release bile.
• Trypsinogen is converted to trypsin by enteropeptidase.
• Trypsin cleaves proteins using specific amino acid sites.

Amino Acid Pool

• Body proteins can be degraded, providing amino acids for the pool.
• Dietary proteins are digested, absorbed, and enter the pool.
• This pool is used for protein synthesis.
• Non-protein nitrogenous compounds can be synthesized from this pool.

Catabolism of Amino Acids

• Catabolism of amino acids leads to a net nitrogen loss that must be compensated by diet.
• Amino acids contain an amino group that distinguishes their catabolism from other catabolic processes.
• Each degradative pathway involves a key step where the amino group is separated from the carbon skeleton and processed in specialized pathways.
• The catabolic pathways of amino acid degradation include transamination and deamination.
• Amino acids are converted to intermediates of the citric acid cycle or glucose.

Catabolism of the Amino Group

• Transamination is the transfer of an amino group from an amino acid to an α-keto acid.
• It's catalyzed by transaminases (aminotransferases).
• Pyridoxal phosphate (PLP) acts as a co-factor.
• The amino group is transferred to α-ketoglutarate, generating glutamate and the α-keto acid analog of the original amino acid.

Deamination

• Deamination removes the amino group as ammonia.
• Oxidative deamination involves the removal of ammonia from glutamate, catalyzed by glutamate dehydrogenase.
• This reaction requires NAD+ or NADP+ and generates α-ketoglutarate.
• Non-oxidative deamination is the direct removal of the amino group.
• This typically occurs in amino acids with hydroxyl groups (e.g., serine, threonine).

Direct Removal of an Amide Function Group

• Glutamine synthetase catalyzes the conjugation of ammonia and glutamate to produce glutamine.
• Glutamine acts as a carrier for ammonia, transported from peripheral tissues to the liver.
• Glutaminase, in the liver, hydrolyzes glutamine, releasing ammonia for urea synthesis.

Role of Glutamate

• Glutamate acts as a collector for amino groups from amino acids.
• It is the only amino acid that undergoes oxidative deamination at significant rates in mammalian tissues.

Non-Oxidative Deamination

• This process involves the direct removal of the amino group from hydroxyl-containing amino acids (serine, threonine, homoserine).
• The reaction is catalyzed by PLP-dependent dehydratases.

Decarboxylation

• Decarboxylation removes a carboxyl group, producing important biological amines (e.g., neurotransmitters).
• It involves the removal of CO2 from amino acids to yield amines.

Metabolism of Ammonia

• Ammonia exists as NH₄⁺ at physiological pH.
• It is produced from amino acids, biogenic amines, and other processes.
• Ammonia is very toxic and needs to be removed.
• The liver converts ammonia into urea via the urea cycle.
• Glutamine and alanine transport ammonia to the liver.

Transport of Ammonia

• Glutamine acts as a storage and transport form of ammonia.
• Glutaminase in the liver cleaves glutamine to release ammonia.
• Alanine transports ammonia to the liver in the glucose-alanine cycle.

The Glucose-Alanine Cycle

• Skeletal muscle produces pyruvate, lactate, and ammonia.
• Alanine in the cycle is used to transport ammonia to the liver.
• Pyruvate is used for gluconeogenesis in the liver.
• Glucose is returned to the muscle.

Nitrogen Excretion

• The three forms of nitrogen excretion in animals are ammonia, urea, and uric acid.
• Plants recycle nitrogen and typically excrete nitrogen only in unusual circumstances.

The Urea Cycle

• Ammonia is converted to urea in the liver mitochondria via the urea cycle.
• The urea cycle is the first metabolic pathway to be elucidated.
• The cycle has five enzymatic steps that interconvert various intermediates.
• Intermediates of the urea cycle are also used in the citric acid cycle.

Steps in the Urea Cycle

• Carbamoyl phosphate synthetase I captures ammonia, producing carbamoyl phosphate.
• Ornithine transcarbamoylase converts ornithine to citrulline.
• Argininosuccinate synthetase condenses an aspartate to citrulline to form argininosuccinate.
• Argininosuccinase cleaves argininosuccinate to yield arginine and fumarate.
• Arginase converts arginine to ornithine and urea.

Regulation of Urea Cycle

• Carbamoyl phosphate synthase I is the rate-limiting enzyme in the urea cycle.
• N-acetylglutamate activates the enzyme.
• The rate of urea synthesis correlates with N-acetylglutamate concentration.

End Products of Amino Acid Degradation

• Some amino acids have multiple degradation pathways.
• Ketogenic amino acids can produce ketone bodies.
• Glucogenic amino acids can lead to glucose formation.
• Different amino acids degrade into various intermediate products.

Summary of Amino Acid Catabolism

• Amino acids are catabolized into intermediates of the citric acid cycle or glucose. Some amino acids form ketone bodies, and some have multiple end products.
• Some genetic disorders can affect amino acid catabolism, leading to deficiencies in certain enzymes.