Urea Cycle

The Urea Cycle

urea formation Reaction

HCO3- + 1 NH3 + Aspartate + 3ATP + H2O ?
Urea + Fumarate + 2ADP + AMP + 2 Phosphate and 1 Pyrophosphate.

Urea is the end-product of the catabolism of nitrogen, which

enters the urea cycle as ammonium.

Occurs in liver cells (aka hepatocytes).
The urea cycle is particularly active after a high protein meal and during a states of starvation.

– The first two reactions of the cycle occur in the mitochondrial matrix and the remaining occur in the cytosol.

Carbamoyl phosphate synthase I (CPS I)

Indicate that carbamoyl phosphate synthase I (CPS I) catalyzes the first reaction the first reaction: carbamoyl phosphate synthesis.
Indicate that it is the rate-limiting step, thus CPS I is, in essence the pacemaker enzyme of the urea cycle.

Substrates: bicarbonate, free ammonia, and ATP

Show that the substrates are bicarbonate, free ammonia (which derives primarily from glutamine and asparagine) and ATP (which makes it essentially an irreversible reaction).

Note it's often reported that the condensation is between carbon dioxide and ammonium, probably because nitrogen is transported throughout the body as ammonium (not ammonia) but here we show the condensation as occurring between bicarbonate and ammonia because carbamoyl synthetase actually uses ammonia (not ammonium) as its substrate.

Carbamoyl phosphate

These substrates combine to produce the first intermediate:

Carbamoyl phosphate, which is: – Carbamoyl: carbon bonded to an amide and double bonded to an oxygen. – Phosphate: phosphorous with 4 oxygen.

We highlight that the carbon and nitrogen were derived from bicarbonate and ammonia.

In the process, ADP, hydrogen, and phosphate are released.

N-acetyl glutamate

The cofactor N-acetyl glutamate is necessary for CPS I to proceed (it's sufficiently present after a protein meal, especially).
The enzyme N-acetyl glutamate synthase (NAGS) synthesizes it from glutamate and acetyl CoA.
Arginine positively regulates this reaction.

– Arginine is a marker of high protein conditions, and thus positively regulates the urea cycle.

citrulline formation

Now, for the second key reaction in the cycle: citrulline formation.

Anhydride bond

An anhydride bond connects the carbamoyl and phosphate groups – which makes the carbamoyl primed for transfer.

Ornithine

It easily moves to ornithine to form citrulline (still within the mitochondrial matrix) via ornithine transcarbamoylase and the phosphate is lost.
Next citrulline exits the matrix and enters the cytosol.

We introduce an aspartate and specify its amino group, which we'll track through the urea cycle.

Argininosuccinate synthetase

Argininosuccinate synthetase catalyzes the reaction to combine aspartate with citrulline to form argininosuccinate.
One ATP is converted to AMP and pyrophosphate to drive forward the reaction (pyrophosphate is later hydrolyzed, as well).

We draw the terminal carbon of argininosuccinate so we can see that its two nitrogens form from both the free ammonia from the beginning of the cycle and the aspartate.

Argininosuccinase

Argininosuccinase cleaves this large molecule into arginine and fumarate.

We choose to show fumarate in block lettering because we've seen elsewhere its importance as a carbon skeleton intermediate in the TCA cycle and its role in the integration of metabolism.

Arginase hydrolyzes arginine to ornithine and urea.
Urea carries that two nitrogen picked up during the urea cycle: one from ammonia and one from aspartate.

Again, we draw the terminal carbon of arginine bound to two highlighted amine groups (from free ammonia and from aspartate).

Urea

Urea is simply our two highlighted amine groups joined by a carbonyl carbon (originally from bicarbonate).

– Urea can safely diffuse into circulation and travel to the kidneys, where it is excreted as urine.

To emphasize this point, we write that urea gains one nitrogen from free ammonia and one nitrogen from aspartate.

Oornithine reenters the cycle at citrulline formation.

Urea Cycle

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