Hepatic Amino Acid Metabolism: Deamination, Transamination & Urea Cycle

The liver is the central hub for amino acid homeostasis, balancing protein synthesis, energy production, and nitrogen disposal.

Major Metabolic Pathways

1. Transamination (Reversible Amino Group Transfer)

• Enzymes: Aminotransferases (AST, ALT) — require pyridoxal phosphate (PLP/B6)
• Reaction: Amino acid + α-ketoacid ⇄ New amino acid + New ketoacid
• Key pairs: Alanine ⇄ Pyruvate; Aspartate ⇄ Oxaloacetate; Glutamate ⇄ α-Ketoglutarate
• Function: Redistributes amino groups; funnels nitrogen to glutamate

2. Oxidative Deamination (Irreversible Nitrogen Liberation)

• Primary enzyme: Glutamate dehydrogenase (GDH) — mitochondrial
• Reaction: Glutamate + NAD⁺/NADP⁺ + H₂O → α-Ketoglutarate + NH₄⁺ + NAD(P)H
• Regulation: Activated by ADP/GDP; inhibited by GTP/ATP (energy status sensor)
• Net: Releases free ammonia for urea synthesis

3. Urea Cycle (Ornithine Cycle) — Hepatic Nitrogen Disposal

• Location: Mitochondria (first 2 steps) + Cytosol (last 3 steps)
• Inputs: 2 NH₄⁺ (one via carbamoyl phosphate, one via aspartate), 3 ATP, CO₂
• Output: Urea + 2 ADP + AMP + 2 Pi + PPi
• Key enzymes: CPS1, OTC, ASS, ASL, ARG1
• Regulation: N-acetylglutamate (CPS1 activator); substrate availability

4. Carbon Skeleton Fates

5. Specialized Hepatic Amino Acid Handling

• Glutamine synthetase (perivenous): Scavenges residual NH₄⁺ → glutamine (brain fuel, renal ammoniagenesis)
• Glutaminase (periportal): Releases NH₄⁺ for urea cycle
• Alanine cycle (Cahill cycle): Muscle → alanine → liver → pyruvate → glucose → muscle

Clinical Correlates

• Elevated AST/ALT: Hepatocellular injury releases aminotransferases
• Hyperammonemia: Urea cycle defects, liver failure, portosystemic shunting
• BCAA/AAA ratio: Decreased in cirrhosis (aromatic AA ↑, branched-chain ↓) → hepatic encephalopathy

Hepatic amino acid metabolism exemplifies metabolic integration: nitrogen disposal, glucose homeostasis, and energy production are inseparable.

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Pathway	Precursors	Conditions
Gluconeogenesis	Glucogenic AAs (Ala, Gln, Asp, etc.)	Fasting, low carb
Ketogenesis	Ketogenic AAs (Leu, Lys) + mixed	Prolonged fasting, keto diet
Complete oxidation	All AAs via TCA cycle	Energy demand
Protein synthesis	All essential + non-essential	Fed state, growth/repair