Amino Acids and Metabolism Quiz

Amino Acid Oxidation and Urea Production

• Amino acid catabolism has two main parts: one involving amino groups and the other involving carbon skeletons.
• All amino acid degradation pathways involve a key step using pyridoxal phosphate (a cofactor).
• In this step, the amino group is separated from the carbon skeleton and channeled into pathways for amino group metabolism.
• The carbon skeletons are broken down into citric acid cycle intermediates.
• Free ammonia is toxic, so excess amino groups need safe excretion. The urea cycle in mammals serves this purpose.
• Each amino acid has a unique catabolic fate. All can be oxidized to generate ATP. All but leucine and lysine can contribute to gluconeogenesis.
• Key amino acids involved in nitrogen transport and distribution include alanine, glutamate, glutamine, and aspartate. These are present in high concentrations in mammalian tissues and are readily converted to citric acid cycle intermediates.
• Metabolic pathways are not isolated; their processes are interwoven with other catabolic and anabolic pathways.

Metabolic Circumstances of Amino Acid Oxidation

• Amino acids undergo oxidative degradation when:
  • amino acids released from protein turnover are not needed for new protein synthesis
  • ingested amino acids exceed the body's needs for protein synthesis
  • cellular proteins are used for fuel when carbohydrates are unavailable or improperly utilized

Metabolic Fates of Amino Groups

• Glutamate and glutamine channel amino groups to a single excretory product
• Free ammonia is toxic
• Excess amino groups must be excreted safely. In mammals, the urea cycle serves this purpose.

Ammonotelic, Ureotelic, and Uricotelic Animals

• Ammonotelic animals excrete amino nitrogen as ammonia (most aquatic species).
• Ureotelic animals excrete amino nitrogen as urea (most terrestrial animals, including humans).
• Uricotelic animals excrete amino nitrogen as uric acid (birds and reptiles).

Dietary Protein Degradation

• Protein degradation in the gastrointestinal tract involves several hormones and enzymes:
  • Gastrin: a hormone secreted when dietary protein enters the stomach, stimulating the secretion of HCI and pepsinogen.
  • Pepsinogen: a zymogen converted to active pepsin by autocatalytic cleavage at low pH.
  • Secretin: a hormone secreted into the blood in response to low pH in the small intestine, stimulating the pancreas to secrete bicarbonate into the small intestine.
  • Pancreatic proteases: several proteases (e.g., trypsinogen, chymotrypsinogen) are stimulated by cholecystokinin, secreted into the blood in response to peptides in the small intestine.
• These processes break down dietary protein to amino acids.
• The intestinal mucosa absorbs free amino acids and transports them into the blood. They travel to the liver.

Acute Pancreatitis

• Acute pancreatitis is caused by obstruction of the pathway for pancreatic secretions to enter the intestine.
• Premature conversion of zymogens to active forms leads to self-digestion of the pancreas.

Pyridoxal Phosphate (PLP)

• PLP is the coenzyme form of pyridoxine or vitamin B6.
• It serves as a prosthetic group for all aminotransferases.
• PLP carries amino groups at the active site.

Transamination Reactions

• Transamination reactions transfer the α-amino group to the α-carbon atom of α-ketoglutarate.
• The resulting product is an α-keto acid analog of the amino acid.
• Reactions are freely reversible (ΔG' ~ 0 kJ/mol).
• The reactions effectively collect amino groups from many amino acids in the form of L-glutamate.

Urea Cycle

• The urea cycle is the pathway by which ammonia, deposited in hepatocyte mitochondria, is converted to urea.

• Urea is then excreted into the urine.

• Enzymes are clustered within metabolons.

• The urea cycle takes place in two cellular compartments.

Urea Cycle Enzymatic Steps

• Carbamoyl phosphate synthetase I: catalyzes the formation of carbamoyl phosphate from NH4+ and CO2 (requires 2 ATP). Takes place in the mitochondrial matrix.

• Ornithine transcarbamoylase:catalyzes the formation of citrulline and P₁ from ornithine and carbamoyl phosphate. Takes place in the mitochondrial matrix.

• Argininosuccinate synthetase:catalyzes the condensation of the amino group of aspartate and the ureido group of citrulline to form argininosuccinate. (requires ATP; uses a citrullyl-AMP intermediate) Takes place in the cytosol.

• Argininosuccinase: catalyzes the reversible cleavage of argininosuccinate to form arginine and fumarate. Fumarate is converted to malate and joins the pool of citric acid cycle intermediates. Takes place in the cytosol.

• Arginase: catalyzes the cleavage of arginine to form urea and ornithine. Ornithine is transported into the mitochondrion to initiate another round of the cycle in the mitochondrial matrix.

Glutamine

• Glutamine synthetase catalyzes the combination of free ammonia with glutamate to yield glutamine (requires ATP).
• Critical for transporting toxic ammonia to the liver.
• Glutaminase catalyzes the conversion of glutamine back to glutamate and NH4+.

Alanine

• Alanine aminotransferase interconverts pyruvate and alanine.
• An important molecule in the transport of amino groups to the liver.

Glucose-Alanine Cycle

• A pathway by which alanine carries ammonia and the carbon skeleton of pyruvate to the liver.
• Ammonia is excreted, and pyruvate is used to produce glucose that then returns to the muscle.

Amino Acid Degradation to Pyruvate

• Six amino acids (alanine, tryptophan, cysteine, serine, glycine, and threonine) are converted to pyruvate.
• Pyruvate can either be converted to:
  • Acetyl-CoA for oxidation via the citric acid cycle.
  • Oxaloacetate to enter gluconeogenesis

Serine Dehydratase

• Serine dehydratase catalyzes the conversion of serine to pyruvate.
• It removes both the β-hydroxyl and α-amino groups of serine.
• This reaction is a pyridoxal phosphate-dependent reaction.

Glycine

• Glycine can be degraded via serine hydroxymethyltransferase (requires tetrahydrofolate and pyridoxal phosphate).
• Glycine can be degraded via glycine cleavage enzyme (requires tetrahydrofolate).
• Glycine can be degraded via D-amino acid oxidase.

Genetic Defects in Amino Acid Metabolism

• Many amino acids are neurotransmitters or precursors or antagonists of neurotransmitters.
• Genetic defects in amino acid metabolism can lead to defective neural development and intellectual deficits.

Phenylketonuria (PKU)

• A disease caused by a genetic defect in phenylalanine hydroxylase.
• Most common cause of elevated phenylalanine levels in the blood.
• Treated with dietary intervention.

Phenylalanine Hydroxylase

• Phenylalanine hydroxylase requires tetrahydrobiopterin as a cofactor.
• It is a mixed-function oxygenase, catalyzing hydroxylation of phenylalanine.

Tetrahydrobiopterin

• Tetrahydrobiopterin (a cofactor) carries electrons from NADPH to O2.
• Dihydrobiopterin reductase catalyzes the reduction of dihydrobiopterin to tetrahydrobiopterin.

Alternative Pathways for Phenylalanine Catabolism in PKU

• Aminotransferase catalyzes the transamination of phenylalanine with pyruvate to form phenylpyruvate.
• Phenylpyruvate is either decarboxylated or reduced.

Maple Syrup Urine Disease

• A disease caused by defects in branched-chain α-keto acid dehydrogenase complex.
• Isoleucine, leucine and valine cannot be degraded in the liver.
• Results in accumulation of α-keto acids.
• Treated with controlled diets.

Asparagine and Aspartate

• Asparagine and aspartate are degraded to the citric acid cycle intermediate oxaloacetate.
• Asparaginase catalyzes the hydrolysis of asparagine to aspartate.
• Aspartate aminotransferase catalyzes the transamination of aspartate with α-ketoglutarate, yielding glutamate and oxaloacetate.