The Urea Cycle

Urea cycle

The two nitrogen’s in urea are derived from ammonia and Aspartate and the carbon from bicarbonate.

The glutamate dehydrogenase reaction that feeds ammonia into the cycle also takes place in the mitochondria. The ammonia released GDH reacts with ammonia to form the carbamoyl group which is activated to carbomyl. The reaction is catalysed by carbomyl synthetase 1. CPS1 is allosterically activated by N-acetyl glutamate (NAG) which is synthesized in large quantities when there is large scale deamination of amino acids. The carrier molecule in the urea cycle is ornithine (like oxaloacetate). Ornithine reacts with carbomyl phosphate to give citrulline in a reaction catalyzed by ornithine transcarbamoylase.

Step 1

Two ATP molecules are used, occurs in the mitochondria.

CO2 (bicarbonate) + NH4+ (carbamoyl phosphate synthetase I [CPS1]) (2ATP - 2ADP + Pi) = carbonyl phosphate

Step 2

Ornithine carries the cycle forward. Ornithine transcarbamoylase acts in the mitochondria, citrulline is transported to the cystol.

Ornithine- (ornithine transcarbamoylase) = citrulline.

Step 3

Aspartate supplies the second nitrogen. Argininosuccinate synthethase is the cytosolic entry point for nitrogen 2. Energy is required for this synthetic reaction.

Citrulline + Aspartate + ATP (argininossuccinate synthetase) = Argininosuccinate + AMP+PPi

Step 4

Fumarate creates the TCA connection. Fumarate leaves the Aspartate derived portion- linking the urea cycle with the TCA cycle.

Argininosuccinate (Argininosuccinate) = fumarate (leaves) + arginine

Step 5

Arginase releases urea and regenerates the carrier. The cycle closes because ornithine is restored. Urea is excreted by the kidney; ornithine can re-enter the mitochondrial part of the cycle.

Arginine + H2O (arginase) = Urine + ornithine

Regulation

CPS1 is the control point.

N-acetylglutamate signals increased nitrogen load.

1. N-acetylglutamate: allosterically activates CPS1

2. Large scale deamination: more amino acid deamination = more NAG synthesis.

3. Metabolic state: high protein intake or prolonged fasting/starvation can induce urea cycle enzymes.

Compartmentation

1. Mitochondria: CPS1 and ornithine transcarbamoylase

2. Cytosol: Argininosuccinate synthetase. Argininosuccinase. Arginase.

Urea cycle defects

Early blocks can be especially severe.

1. Any enzyme defect: the source notes describe severe neurological consequences such as seizure, coma and early death.

2. Early cycle defects: CPS1 and ornithine transcarbamoylase defects can lead to very high blood ammonia.

3. Management: the source notes mention dietary intervention in some cases and enzyme replacements in some settings.