Amino Acid Catabolism
Amino acid catabolism involves the breakdown of amino acids, particularly during fasting, high-protein diet, or when carbohydrates are insufficient. The first step is removal of the amino group (nitrogen); the carbon skeleton then enters the central metabolic pathways.
Step 1 — Transamination
Amino group transferred from an amino acid to α-ketoglutarate → forming Glutamate + new α-keto acid. Catalyzed by Aminotransferases (Transaminases). Coenzyme: PLP (Pyridoxal Phosphate = B6).
- ALT (SGPT): Alanine + α-KG ↔ Pyruvate + Glutamate (liver-specific; best marker of hepatocellular injury)
- AST (SGOT): Aspartate + α-KG ↔ OAA + Glutamate (liver, heart, muscle)
Most amino acids converge their amino groups into Glutamate via transamination before further disposal.
Step 2 — Oxidative Deamination
Glutamate → α-Ketoglutarate + NH₃ [Glutamate Dehydrogenase (GDH), mitochondria, liver]. Releases free ammonia (toxic). Activated by ADP (energy need → promote amino acid catabolism); Inhibited by GTP, NADH, ATP.
Step 3 — Urea Cycle (Disposal of NH₃)
Ammonia is highly toxic to the brain. Converted to urea (non-toxic, excreted by kidneys) in the liver via the urea cycle. Starts in mitochondria, completed in cytosol.
- NH₃ + CO₂ + 2ATP → Carbamoyl Phosphate [Carbamoyl Phosphate Synthetase I, mitochondria — rate-limiting; activated by N-acetylglutamate (NAG)]
- Carbamoyl-P + Ornithine → Citrulline [Ornithine Transcarbamylase, mito] → Citrulline exits to cytosol
- Citrulline + Aspartate + ATP → Argininosuccinate [Argininosuccinate Synthetase] — 2nd N enters from Aspartate
- Argininosuccinate → Arginine + Fumarate [Argininosuccinase] — Fumarate → TCA cycle
- Arginine + H₂O → Ornithine + Urea [Arginase] — Ornithine recycled back to mitochondria
Energy cost: 3 ATP per urea molecule. Each urea contains 2N (one from NH₃, one from Aspartate).
Carbon Skeletons — Glucogenic vs Ketogenic
- Purely Ketogenic: Leucine, Lysine (cannot contribute to gluconeogenesis)
- Both Glucogenic and Ketogenic: Ile, Phe, Thr, Trp, Tyr
- Purely Glucogenic: All others (enter TCA as OAA, α-KG, Succinyl-CoA, Fumarate, Pyruvate)
Hyperammonemia
↑Blood NH₃ → inhibits α-KGDH → TCA cycle impaired → ATP deficiency in brain → encephalopathy, cerebral edema. Urea cycle enzyme deficiencies (all AR except OTC which is X-linked) → congenital hyperammonemia in neonates. Acquired: Liver cirrhosis (main cause in adults) → portal hypertension → gut bacteria produce NH₃ → absorbed. Treated with lactulose (acidifies colon, traps NH₄⁺), rifaximin, dietary protein restriction, Na-benzoate/phenylbutyrate (alternate N excretion pathways).
One-Carbon Metabolism
Serine and Glycine donate one-carbon units via Tetrahydrofolate (THF). Used for purine synthesis, dTMP synthesis, methylation reactions (with S-adenosylmethionine, SAM). SAM is the major methyl group donor in the body (donates methyl to creatine, epinephrine, DNA, phosphatidylcholine).