Nutrition: Protein and Amino Acid Pool

Amino Acid Disposal of Nitrogen

• Amino acids are not stored by the body, requiring intake, synthesis, or breakdown of existing proteins.
• Excess amino acids are rapidly broken down.
• The first stage involves removing the α-amino groups, which forms ammonia and a-keto acids.
• A significant portion of the ammonia is used to synthesize urea.
• The second stage of amino acid catabolism involves breaking down the carbon skeletons of a-keto acids into common energy-producing metabolic pathways.

Overall Nitrogen Metabolism

• Amino acid catabolism is part of a larger nitrogen-containing molecule metabolism.
• Nitrogen intake mostly comes from amino acids in dietary protein.
• Nitrogen excretion happens mostly through urea, ammonia, and other products from amino acid metabolism.
• Body protein functions in transformations via the amino acid pool and protein turnover.

Protein Turnover

• Protein turnover is the simultaneous synthesis and degradation of protein molecules.
• In healthy adults, the total amount of protein remains constant since protein synthesis offsets the rate of protein degradation.
• The rate of protein turnover varies widely for different proteins.
• Short-lived proteins are rapidly degraded, while long-lived proteins (structural proteins) have longer half-lives.
• Protein degradation is done by two major enzyme systems: the ATP-dependent ubiquitin-proteasome system and the ATP-independent degradative enzyme system of the lysosomes.

Amino Acid Pool

• Free amino acids are present throughout the body (cells, blood, extracellular fluids).
• The amino acid pool includes amino acids from protein degradation, dietary protein, and synthesis of nonessential amino acids.
• These amino acids are used for body protein synthesis and consumed for glucose, glycogen, fatty acids, or ketone bodies.
• In healthy individuals, the intake and output of the amino acid pool are balanced, maintaining a constant amount in steady state.

Digestion of Dietary Proteins

• Protein digestion begins in the stomach with gastric secretions.
• Hydrochloric acid denatures proteins.
• Pepsinogen is converted to pepsin, which breaks proteins into smaller peptides and free amino acids.
• Pancreatic enzymes enter the small intestine and continue cleaving large polypeptides into oligopeptides and amino acids.
• Different enzymes (trypsin, chymotrypsin, elastase, and carboxypeptidases) have unique specificities for amino acid R-groups to cleave peptide bonds.
• Enteropeptidase activates trypsinogen to trypsin, initiating a cascade of zymogen activation.
• Abnormalities in pancreatic secretion can lead to incomplete digestion and absorption of fats and proteins, resulting in steatorrhea and undigested protein in feces.

Transport of Amino Acids into Cells

• Free amino acids enter cells by Sodium (Na+)-linked secondary transport systems in the apical membrane.
• Di- and tripeptides enter cells via H+-linked transport systems, which hydrolyze the peptides into amino acids in the cell cytoplasm.
• Free amino acids are released into the portal system via facilitated diffusion.
• Branched-chain amino acids are not metabolized by the liver but travel mostly to muscle.

Removal of Nitrogen from Amino Acids

• The presence of the α-amino group prevents oxidative breakdown and is essential for amino acid catabolism.
• Transamination is the first step, where the α-amino group is transferred to α-ketoglutarate, forming glutamate and an α-keto acid.
• Oxidative deamination of glutamate releases ammonia (NH3), which can be used in urea synthesis.
• Aminotransferases (formerly called transaminases) catalyze the transfer of the amino groups to form glutamate, which then can be oxidatively deaminated.
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) are two crucial aminotransferases.

Urea Cycle

• Urea is the major nitrogenous waste product in mammals.
• The urea cycle occurs in the liver, with the first steps occurring in the mitochondria and the remaining steps in the cytosol.
• Carbamoyl phosphate synthetase I is the rate-limiting step in the urea cycle, requiring ATP for the synthesis of carbamoyl phosphate.
• Ornithine transcarbamoylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase are the other enzymes involved in the cycle.
• Urea is transported to the kidneys for excretion in the urine.

Metabolism of Ammonia

• Ammonia is a major byproduct of amino acid metabolism and is toxic to the central nervous system (CNS).
• The liver is the primary organ for ammonia disposal through urea cycle synthesis.
• Glutamine is an important non-toxic transport form for ammonia.
• Glutamine synthetase synthesizes glutamine from glutamate.
• Glutaminase catalyzes the breakdown of glutamine into glutamate and ammonia.
• Urea synthesis in the liver excretes a significant portion of nitrogenous waste.

Metabolic Defects in Amino Acid Metabolism

• Inborn errors of amino acid metabolism are caused by mutant genes, usually affecting enzymes.
• These defects can result in the loss of enzyme activity or a partial deficiency.
• Without treatment, some defects result in mental retardation or developmental issues due to harmful accumulation of metabolites.
• Conditions like phenylketonuria (PKU), maple syrup urine disease (MSUD), albinism, and homocystinuria are examples of metabolic defects in amino acid metabolism.