AA6 Urea Cycle

In what organ does the urea cycle primarily occur?

The liver (hepatocytes).

Where does urea production begin and end within the cell?

Begins in the mitochondria and continues in the cytosol.

Why is ammonia toxic to cells?

High levels disrupt cellular pH and metabolism; accumulation can be lethal (hyperammonemia).

What are ureotelic organisms?

Organisms, like mammals, that excrete nitrogen mainly as urea.

What do birds and some fish excrete instead of urea?

Birds: uric acid (uricotelic); Fish: ammonia directly (ammonotelic).

What compound carries ammonia safely from tissues to the liver?

Glutamine.

Which enzyme releases ammonia from glutamine in the liver?

Glutaminase.

Which enzyme converts glutamate to α-ketoglutarate, releasing ammonia?

Glutamate dehydrogenase (GDH).

What tissue especially uses ammonia assimilation into glutamine for protection?

The brain.

What is the enzyme that catalyzes the first step before the urea cycle?

Carbamoyl phosphate synthetase I (CPS1).

Where does CPS1 function?

In the mitochondria of liver cells.

What are the substrates of CPS1?

: Ammonia (NH₄⁺), CO₂ (as bicarbonate), and 2 ATP.

What is the product of the CPS1 reaction?

carbamoyl phosphate

Why is CPS1 considered an ammonia assimilation reaction?

It incorporates free ammonia into a stable compound, preventing toxicity.

What is the difference between CPS1 and CPS2?

CPS1 is mitochondrial and used in the urea cycle

CPS2 is cytosolic and used in pyrimidine synthesis.

What enzyme catalyzes the first step of the urea cycle?

Ornithine transcarbamoylase (OTC).

What are the reactants and products of the OTC reaction?

Ornithine + carbamoyl phosphate → citrulline.

Where does this reaction occur?

In the mitochondria.

What happens to citrulline after it is formed?

It is transported to the cytosol via facilitated diffusion.

What enzyme catalyzes citrulline’s reaction with aspartate?

Argininosuccinate synthetase.

What are the substrates of step 2?

Citrulline, aspartate, and ATP.

What is the product of this step?

Argininosuccinate.

Where does the second nitrogen for urea come from?

From aspartate.

What enzyme catalyzes the cleavage of argininosuccinate?

Argininosuccinase.

What are the products of this reaction?

Arginine and fumarate.

What happens to the fumarate produced?

It can be converted to malate and enter the TCA cycle.

What enzyme catalyzes the final step of the urea cycle?

Arginase.

What are the products of the arginase reaction?

Urea and ornithine.

Where does ornithine go after the final step?

Back into the mitochondria to restart the cycle.

What are the two sources of nitrogen in urea?

One from ammonia (via carbamoyl phosphate) and one from aspartate.

What happens to the carbon in urea?

It comes from CO₂ (bicarbonate).

What hormone increases urea cycle enzyme synthesis after a high-protein meal?

Glucagon.

Why does glucagon increase urea cycle enzymes after high-protein intake?

Excess amino acids stimulate glucagon release, which signals for amino acid catabolism and urea formation.

What enzyme is the key regulatory enzyme of the urea cycle?

CPS1 (carbamoyl phosphate synthetase I).

What molecule activates CPS1 allosterically?

N-acetylglutamate (NAG).

What enzyme synthesizes N-acetylglutamate?

N-acetylglutamate synthase (NAGS).

What are the substrates for NAGS?

Glutamate and acetyl-CoA.

What molecule activates NAGS?

Arginine.

Why does arginine activate NAGS?

High arginine levels indicate high amino acid availability, signaling a need to activate the urea cycle.

How is the urea cycle linked to the TCA cycle?

Through fumarate and aspartate intermediates — this link is called the Krebs bicycle or aspartate–argininosuccinate shunt

What benefits come from the link between the urea and TCA cycles?

Shared intermediates reduce the energetic cost of the urea cycle and maintain metabolic balance.

What condition results from defective urea cycle enzymes?

Hyperammonemia (toxic accumulation of ammonia).

Why is regulation of ammonia critical?

To prevent neurotoxicity and maintain nitrogen balance.