Harvey's Garden

Catabolism of amino acids

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Summary of steps (important!)

  1. Generation of ammonia in periphery
  2. Transportation of ammonia to liver
    1. In periphery
      • Transamination: amino acids + α-ketoglutarate ⇄ α-ketoacids + glutamate
    2. Transport to liver, by either
      • Glutamine cycle (most common)
        • Primary Sites: Brain and Peripheral Tissues.
        • Purpose: The major mechanism for scavenging excess ammonia.
        • Glutamate + NH4+ + ATP → Glutamine + ADP + Pi
      • Alanine cycle (Cahill cycle)
        • Primary Site: Skeletal Muscle.
        • Purpose: Transports nitrogen from muscle protein breakdown to the liver while regenerating glucose for muscle energy.
        • Pyruvate + glutamate ⇄ alanine + α-ketoglutarate
    3. In liver
      • Convert back to glutamate, by either
        • Glutaminase: glutamine + H2O → glutamate + ammonium
        • Transamination: alanine + α-ketoglutarate ⇄ pyruvate + glutamate
      • Release ammonia (Deamination): glutamate + NAD(P)+ + H2O ⇄ α-ketoglutarate + NH4+ + NAD(P)H + H+
  3. Excretion of ammonia
    • Urea cycle
FeatureGlutamateGlutamine
Primary RoleMajor excitatory neurotransmitter in CNSNitrogen transport; fuel for gut & immune cells
StructureAcidic (anionic); side chain has -COOHNeutral; side chain has -CONH2 (amide)
MetabolismMade from glutamine (via glutaminase)Made from glutamate (via glutamine synthetase)
Key Assoc.Excitotoxicity (e.g., stroke, seizure)Conditionally essential (in stress/illness)
CNS CycleReleased by neurons → taken up by gliaReleased by glia → taken up by neurons

Transamination

  • Description: transfer of an amino group from an AA to an α-ketoacid for breakdown, or to an α-ketoacid to form a nonessential AA
  • E.g.
    • ALT:
    • AST: aspartate + α-ketoglutarate ⇄ oxalacetate + glutamate

Deamination

  • Description: reaction in which an amino group from an AA is released as ammonium

Cahill cycle and Cori cycle

  1. In the liver, alanine is transaminated by alanine aminotransferase to pyruvate with the amino group being transferred to α-ketoglutarate to form glutamate. Almost all aminotransferase enzymes use α-ketoglutarate as the amino group acceptor.
  2. Thus, amino groups are funneled into glutamate during protein catabolism.
  3. Glutamate is further metabolized by the enzyme glutamate dehydrogenase, which liberates free ammonia and regenerates α-ketoglutarate.
  4. Ammonia then enters the urea cycle to form urea, the primary disposal form of nitrogen in humans.
  5. Urea subsequently enters the blood and is excreted in the urine.

Cori cycle & Cahill cycle

Lactate/alanine is transported to the liver, where it is converted into glucose. It is then transported back to the muscles for energy production.

Urea cycle

  • Function: Converts ammonia (NH3) into urea for excretion. Occurs in the liver (cytosol and mitochondria).
  • Key Steps & Enzymes:
    1. CO2 + NH3 + 2 ATP → Carbamoyl Phosphate. Enzyme: Carbamoyl Phosphate Synthetase I (CPS I). Rate-limiting step.
      • Location: Mitochondria.
      • Activator: N-acetylglutamate.
    2. Carbamoyl Phosphate + Ornithine → Citrulline. Enzyme: Ornithine Transcarbamylase (OTC).

Ornithine transcarbamylase deficiency

  • Genetics: X-linked Recessive (The only urea cycle disorder not Autosomal Recessive).
  • Mechanism: Defect in Ornithine Transcarbamylase → Blocks Carbamoyl phosphate + Ornithine → Citrulline.
  • Key Labs:
    • ↑ Ammonia
    • ↑ Orotic Acid (Excess carbamoyl phosphate shunts to pyrimidine synthesis)
    • ↓ Citrulline
    • ↓ BUN
  • High-Yield Differential:
    • vs. Orotic Aciduria: OTC def. has Hyperammonemia and NO megaloblastic anemia.
    • vs. CPS1 Deficiency: OTC def. has ↑ Orotic acid (CPS1 def. has low orotic acid).
  • Treatment: Low protein diet, nitrogen scavengers.

Arginase deficiency

  • Pathophysiology
    • Defect: Arginase (Urea Cycle).
    • Block: Arginine → Ornithine + Urea.
    • Result: Accumulation of Arginine; mild/no hyperammonemia (unlike other UCDs).
    • Genetics: Autosomal Recessive.
  • Clinical Features
    • Spastic diplegia (classic presentation; mimics Cerebral Palsy).
    • Choreoathetosis, growth delay, intellectual disability.
    • Onset: Toddler/Early childhood (not neonatal).
  • Diagnostics
    • Labs: Markedly ↑ Plasma Arginine.
  • Treatment
    • Low protein diet.
    • NO arginine supplementation.

Digestion and absorption of dietary proteins

  1. Mouth: Chewing (mechanical breakdown). No chemical protein digestion.
  2. Stomach:
    • HCl: Denatures proteins and activates pepsinogen to pepsin.
    • Pepsin: Breaks proteins into smaller polypeptides.
  3. Small Intestine (Lumen - major digestion):
    • Pancreas releases inactive enzymes (trypsinogen, chymotrypsinogen, etc.).
    • Enteropeptidase (from intestinal cells) activates trypsinogen to Trypsin.
    • Trypsin then activates other pancreatic enzymes (chymotrypsin, carboxypeptidase).
    • These enzymes break polypeptides into smaller peptides (tripeptides, dipeptides) and some free amino acids.
  4. Small Intestine (Brush Border & Inside Mucosal Cells - final breakdown & absorption):
    • Brush border enzymes (aminopeptidases, dipeptidases, tripeptidases) on intestinal cells break small peptides into mostly free amino acids, plus some di- and tripeptides.
    • Free amino acids, dipeptides, and tripeptides are absorbed into intestinal mucosal cells (enterocytes).
    • Inside enterocytes: Cytosolic peptidases break down remaining di- and tripeptides into free amino acids.
  5. Bloodstream: Free amino acids are transported from enterocytes into the blood and travel to the liver and then to the rest of the body.

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