Amino acid metabolism

Amino Acid Breakdown - The Nitrogen Shuffle

• Goal: Remove the α-amino group from amino acids, creating a carbon skeleton (α-ketoacid) for energy and a nitrogen atom for disposal.
• Two-step process: Transamination & Oxidative Deamination.

1. Transamination: The "Shuffle"

• Amino group is transferred from an amino acid to α-ketoglutarate.
• Forms glutamate and a new α-ketoacid.
• Enzymes: Aminotransferases (e.g., ALT, AST).
• Cofactor: Pyridoxal Phosphate (PLP), Vitamin B6.

2. Oxidative Deamination

• Occurs mainly in liver mitochondria.
• Glutamate is deaminated by Glutamate Dehydrogenase to regenerate α-ketoglutarate and release free ammonia ($NH_4^+$).
• $NH_4^+$ enters the urea cycle.

⭐ High-Yield: Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) are key liver function tests (LFTs). Elevated levels indicate hepatocellular damage as the enzymes leak from injured cells into the bloodstream.

Urea Cycle - Ammonia's Last Stop

• Primary Site: Liver (mitochondria & cytoplasm).
• Function: Converts neurotoxic ammonia (NH₃) into excretable urea. Connects to TCA cycle via the "Aspartate-Argininosuccinate Shunt".

• Rate-Limiting Enzyme: Carbamoyl Phosphate Synthetase I (CPS I).
  • Activator: N-acetylglutamate (NAGS).
• 📌 Mnemonic: Ordinarily, Careless Crappers Are Also Frivolous About Urination (Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, Urea).

⭐ Exam Favorite: Ornithine Transcarbamylase (OTC) deficiency is the most common urea cycle disorder (X-linked). Leads to ↑ carbamoyl phosphate, which is shunted to pyrimidine synthesis, causing ↑ orotic acid in blood/urine. Presents with hyperammonemia and no megaloblastic anemia.

Glucogenic vs. Ketogenic - Fueling the Body

• Glucogenic AAs: Catabolized to pyruvate or Krebs cycle intermediates (e.g., α-ketoglutarate) to serve as glucose precursors.
• Ketogenic AAs: Degraded to acetyl-CoA or acetoacetate, which can be converted to ketone bodies.
  • 📌 The only purely ketogenic AAs are Leucine and Lysine.
• Both: Phenylalanine, Isoleucine, Tryptophan, Threonine, Tyrosine (📌 PITTT).

⭐ Acetyl-CoA from ketogenic amino acids cannot produce net glucose, as the pyruvate dehydrogenase (PDH) reaction is irreversible.

Key AA Disorders - The Famous Few

• Phenylketonuria (PKU): ↓ Phenylalanine hydroxylase. Mousy/musty body odor. Requires low Phe, high Tyr diet. Avoid aspartame.
• Maple Syrup Urine Disease (MSUD): ↓ Branched-chain α-ketoacid dehydrogenase. Urine smells like burnt sugar. 📌 I Love Vermont maple syrup (Isoleucine, Leucine, Valine).
• Alkaptonuria (Ochronosis): ↓ Homogentisate oxidase. Bluish-black connective tissue, dark urine on standing, debilitating arthralgias.
• Homocystinuria: Most commonly ↓ Cystathionine synthase. Marfanoid habitus, ectopia lentis (downward), thrombosis, intellectual disability.

⭐ Homocystinuria vs. Marfan syndrome: Look for intellectual disability and thrombotic events to favor Homocystinuria.

• Transamination reactions require Vitamin B6 (PLP) to transfer amino groups to α-ketoglutarate.
• The Urea Cycle disposes of nitrogen; its rate-limiting step is Carbamoyl Phosphate Synthetase I (CPS I).
• Urea cycle defects cause hyperammonemia (asterixis, encephalopathy). Ornithine transcarbamoylase deficiency is most common.
• Phenylketonuria (PKU): Phenylalanine hydroxylase deficiency; causes intellectual disability, musty body odor.
• Maple Syrup Urine Disease (MSUD): Branched-chain α-ketoacid dehydrogenase deficiency; burnt sugar urine odor.
• Alkaptonuria: Homogentisate oxidase deficiency; causes black urine and ochronosis.
• Leucine and lysine are exclusively ketogenic amino acids.