Describe the urea cycle with its reactions, site and energetics. Explain its regulation and add a note on the urea cycle disorders.

Definition and Purpose

The Five Steps

• NH3 + CO2 + 2 ATP → 1.
• Carbamoyl phosphate synthetase I (mitochondria) — rate-limiting → Carbamoyl phosphate → 2.
• Ornithine transcarbamoylase (OTC) + ornithine (mitochondria) → citrulline → leaves the mitochondrion → 3.
• Argininosuccinate synthetase + aspartate + ATP (cytosol) → Argininosuccinate → 4.
• Argininosuccinate lyase → arginine + fumarate → 5.
• Arginase → urea + ornithine (ornithine re-enters)

Key Points on Each Step

Sources of the Two Nitrogens

• First nitrogen — free ammonia, mostly from oxidative deamination of glutamate
• Second nitrogen — from aspartate
• The carbon of urea comes from CO2 (as bicarbonate)

Energetics

• 3 ATP are used but 4 high-energy bonds are consumed, because the third ATP goes to amp
• Partly recovered — the fumarate released rejoins the TCA cycle and yields NADH through malate dehydrogenase

Link with the TCA Cycle — the "krebs Bicycle"

Argininosuccinate lyase releases fumarate → Fumarate → malate → oxaloacetate (TCA cycle) → OAA + glutamate → aspartate (transamination by ast) → Aspartate re-enters the urea cycle

• The two cycles are therefore interlocked, sharing fumarate and aspartate

Regulation

Properties and Fate of Urea

• A small, neutral, highly water-soluble molecule; non-toxic even at high concentration
• Contains 2 nitrogen atoms — an efficient carrier
• Freely filtered at the glomerulus; about 40–50% is reabsorbed passively, more when urine flow is low
• Contributes to the medullary osmotic gradient through urea recycling
• A small amount diffuses into the gut, where bacterial urease releases ammonia

• A urea : creatinine ratio above 20:1 suggests a prerenal cause

Applied Aspects

• Urea cycle disorders present in the newborn with vomiting, lethargy, seizures and coma, with hyperammonaemia and respiratory alkalosis (ammonia stimulates the respiratory centre) — a useful clue distinguishing them from organic acidaemias, which cause acidosis
• OTC deficiency — commonest; X-linked; carbamoyl phosphate accumulates and spills into pyrimidine synthesis → orotic aciduria without megaloblastic anaemia
• Citrullinaemia (argininosuccinate synthetase) and argininosuccinic aciduria (lyase) are the next commonest
• Treatment — low-protein diet, sodium benzoate and sodium phenylacetate to provide alternative routes of nitrogen excretion, arginine supplementation, and dialysis in crisis
• Hepatic failure → the urea cycle fails → hyperammonaemia and hepatic encephalopathy; blood urea is low, not high
• N-acetylglutamate synthase deficiency mimics CPS-I deficiency and responds to carglumic acid
• Arginase deficiency (argininaemia) is the rarest and presents later, with spastic diplegia rather than neonatal coma
• Liver transplantation is curative in severe urea cycle defects