Amino Acid Metabolism & Urea Cycle
Detoxifying ammonia and the classic aminoacidopathies
Nitrogen transport and the urea cycle
Collecting nitrogen. When amino acids are broken down, their amino groups are transferred onto α-ketoglutarate to form glutamate (transamination, which requires B6 as pyridoxal phosphate). Muscle exports nitrogen to the liver as alanine (the glucose-alanine, or Cahill, cycle); most other tissues use glutamine. In the liver these carriers release ammonia into the urea cycle.
The urea cycle. It converts toxic ammonia into water-soluble urea for renal excretion. It runs in the liver and spans two compartments — the first two steps in mitochondria, the rest in the cytosol. Carbamoyl phosphate synthetase I (CPS1) is the rate-limiting enzyme. Urea's two nitrogens come from ammonia (via carbamoyl phosphate) and from aspartate.
- NH3 + CO2 → carbamoyl phosphateCPS1; mitochondria; rate-limiting; needs N-acetylglutamate
- + ornithine → citrullineOrnithine transcarbamylase (OTC); mitochondria
- + aspartate → argininosuccinateArgininosuccinate synthetase; cytosol
- → arginine + fumarateArgininosuccinate lyase
- Arginine → urea + ornithineArginase; ornithine re-enters the cycle
Mnemonic for the order: Ordinarily, Careless Crappers Are Also Frivolous About Urination — Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, Urea.
N-acetylglutamate (NAG). CPS1 is inactive without this allosteric activator, made by N-acetylglutamate synthase (NAGS). NAGS deficiency therefore mimics a urea cycle enzyme defect, with hyperammonemia. Mitochondrial CPS1 (urea cycle) is distinct from cytosolic CPS2, which begins pyrimidine synthesis.
Hyperammonemia
Why ammonia is toxic. Excess ammonia pulls α-ketoglutarate into glutamate, depleting it and stalling the TCA cycle in neurons.
Causes and signs. Hyperammonemia may be acquired (liver disease) or hereditary (urea cycle enzyme defects). Signs: tremor and asterixis, slurred speech, somnolence, vomiting, and cerebral edema. Neonates with urea cycle defects stop feeding, become lethargic, and breathe fast (respiratory alkalosis) within the first days of life.
Treatment.
- Low-protein diet — less nitrogen to dispose of.
- Lactulose — acidifies the colon, trapping NH3 as NH4+ for excretion.
- Rifaximin — kills urease-producing gut bacteria (rifaximin, not rifampin).
- Benzoate or phenylbutyrate — conjugate amino acids into excretable compounds, carrying nitrogen out in the urine.
Urea cycle defects and orotic aciduria
OTC deficiency. The most common urea cycle disorder and the only X-linked one. Carbamoyl phosphate that cannot enter the cycle spills into pyrimidine synthesis, so orotic acid rises in blood and urine, alongside hyperammonemia and a low BUN. Classic story: a newborn boy who becomes lethargic and tachypneic around day 3.
Hereditary orotic aciduria. Deficiency of UMP synthase, the pyrimidine-synthesis enzyme that normally converts orotic acid onward, also raises orotic acid — but the urea cycle is intact, so ammonia is normal. Impaired pyrimidine (and so DNA) synthesis instead causes megaloblastic anemia that does not respond to B12 or folate. Treat with uridine.
| Feature | OTC deficiency | UMP synthase deficiency |
|---|---|---|
| Pathway | Urea cycle | Pyrimidine synthesis |
| Inheritance | X-linked recessive | Autosomal recessive |
| Ammonia / BUN | High ammonia, low BUN | Normal ammonia |
| Megaloblastic anemia | No | Yes, unresponsive to B12/folate |
| Treatment | Low protein, nitrogen scavengers | Uridine |
Classic aminoacidopathies
- Phenylalanine → tyrosinePhenylalanine hydroxylase with BH4 cofactor; blocked in PKU
- Tyrosine → homogentisateTyrosine also feeds melanin, catecholamines, and thyroid hormone
- Homogentisate → maleylacetoacetateHomogentisate oxidase; blocked in alkaptonuria
- → fumarate + acetoacetateEnd products enter the TCA cycle and ketone pool
| Disorder | Defect | Accumulates | Key findings | Treatment |
|---|---|---|---|---|
| PKU | Phenylalanine hydroxylase or BH4 cofactor | Phenylalanine | Musty odor, fair skin, eczema, seizures, intellectual disability | Restrict phenylalanine (avoid aspartame); supplement tyrosine |
| Alkaptonuria | Homogentisate oxidase | Homogentisic acid | Ochronosis (dark connective tissue), dark arthropathy, urine black on standing; largely benign | Supportive |
| Homocystinuria | Usually cystathionine synthase | Homocysteine | Marfanoid habitus, intellectual disability, osteoporosis, thrombosis, lens down and in | By type: B6, B9, B12, low methionine |
| Maple syrup urine disease | Branched-chain α-ketoacid dehydrogenase (B1 cofactor) | Isoleucine, leucine, valine and their ketoacids | Sweet maple-syrup urine, vomiting, severe CNS damage | Restrict branched-chain amino acids; thiamine |
| Cystinuria | Renal and intestinal COLA transporter | Cystine in urine | Hexagonal crystals, recurrent stones, positive cyanide-nitroprusside test | Hydration, urinary alkalinization, penicillamine |
PKU. With phenylalanine hydroxylase blocked, tyrosine becomes essential; newborn screening catches the disease before damage. Uncontrolled maternal PKU during pregnancy causes fetal microcephaly and congenital heart disease, so affected women need tight dietary control before conception.
Homocystinuria. In cystathionine synthase deficiency both homocysteine and methionine rise, and many patients respond to high-dose B6, the enzyme's cofactor — the best initial treatment trial.
Lens dislocation: homocystinuria (cystathionine synthase) goes down and in, with thrombosis; Marfan syndrome (fibrillin-1) goes up and out, with aortic root dilation.
Memory aids. MSUD: I Love Vermont maple syrup (Isoleucine, Leucine, Valine — the branched-chain amino acids). Cystinuria: COLA = Cystine, Ornithine, Lysine, Arginine, the dibasic amino acids left unreabsorbed.
Essential and ketogenic amino acids
Essential amino acids. These must come from the diet: PVT TIM HaLL — Phe, Val, Thr, Trp, Ile, Met, His, Leu, Lys (nine). Arginine is only conditionally essential, needed from the diet mainly during growth.
Ketogenic vs glucogenic. Leucine and lysine are the only purely ketogenic amino acids — their carbons end up as acetyl-CoA or acetoacetate, which cannot make glucose. Isoleucine, phenylalanine, threonine, tryptophan, and tyrosine are both ketogenic and glucogenic; the rest are glucogenic.