Urea cycle 1

Urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals
that produces urea ((NH2)2CO) from ammonia (NH3). This cycle was the first metabolic cycle discovered (Hans
Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent
in the kidney.

Function
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like
urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn
errors of metabolism), and in liver failure. The result of liver failure is accumulation of nitrogenous waste, mainly
ammonia, which leads to hepatic encephalopathy.

Reactions
The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino
groups, one from NH4+ and one from Asp, and a carbon atom from HCO3−, to the relatively nontoxic excretion
product urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP).
Ornithine is the carrier of these carbon and nitrogen atoms.

Reactions of the urea cycle

Step Reactants Products Catalyzed by Location

1 carbamoyl phosphate + 2ADP + Pi CPS1 mitochondria

NH4+ + HCO3− + 2ATP

2 carbamoyl phosphate + ornithine citrulline + Pi OTC mitochondria

3 citrulline + aspartate + ATP argininosuccinate + AMP + PPi ASS cytosol

4 argininosuccinate Arg + fumarate ASL cytosol

5 Arg + H2O ornithine + urea ARG1 cytosol

The reactions of the urea cycle

Urea cycle 2

1 L-ornithine
2 carbamoyl phosphate
3 L-citrulline
4 argininosuccinate
5 fumarate
6 L-arginine
7 urea
L-Asp L-aspartate
CPS-1 carbamoyl phosphate synthetase I
OTC Ornithine transcarbamylase
ASS argininosuccinate synthetase
ASL argininosuccinate lyase
ARG1 arginase 1

In the first reaction, NH4+ + HCO3− is equivalent to NH3

+ CO2 + H2O.
Thus, the overall equation of the urea cycle is:
• NH3 + CO2 + aspartate + 3 ATP + 2 H2O → urea +
fumarate + 2 ADP + 2 Pi + AMP + PPi
Since fumarate is obtained by removing NH3 from
aspartate (by means of reactions 3 and 4), and PPi + H2O
→ 2 Pi, the equation can be simplified as follows:
• 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi
+ AMP
Note that reactions related to the urea cycle also cause the reduction of 2 NADH, so the urea cycle releases slightly
more energy than it consumes. These NADH are produced in two ways:
• One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to
ammonium and α-ketoglutarate. Glutamate is the non-toxic carrier of amine groups. This provides the ammonium
ion used in the initial synthesis of carbamoyl phosphate.
• The fumarate released in the cytosol is converted to malate by cytosolic fumarase. This malate is then converted
to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol. Oxaloacetate is
one of the keto acids preferred by transaminases, and so will be recycled to aspartate, maintained the flow of
nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5 ATP, a net production of one high energy
phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing
equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via transamination or to be converted to phosphoenol pyruvate,
which is a substrate to glucose.
An excellent way to memorize the Urea Cycle is to remember the mnemonic phrase "Ordinarily Careless Crappers
Are Also Frivolous About Urination." The first letter of each word corresponds to the first letter of each of the main
reactants or products that are combined with each other or produced as one progresses through the five reactions of
the cycle (Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, Urea).
Urea cycle 3

Regulation

N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which
allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by Arg - allosteric stimulator of NAGS,
and Glu - a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when
free amino acids are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an
activator for the urea cycle.

Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited
deficiencies in the cycle enzymes other than ARG1 do not result in significant decrease in urea production (the total
lack of any cycle enzyme results in death shortly after birth). Rather, the deficient enzyme's substrate builds up,
increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the
way back up the cycle to NH4+, resulting in hyperammonemia (elevated [NH4+]P).
Although the root cause of NH4+ toxicity is not completely understood, a high [NH4+] puts an enormous strain on the
NH4+-clearing system, especially in the brain (symptoms of urea cycle enzyme deficiencies include mental
retardation and lethargy). This clearing system involves GLUD1 and GLUL, which decrease the 2OG and Glu pools.
The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the rate of TCAC, whereas
Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter. [1](p.734)

Pathology
Anomalies of the urea cycle cause urea cycle disorders:
• ornithine transcarbamoylase deficiency
• Carbamoyl phosphate synthetase deficiency (Ornithine translocase deficiency)
• Argininosuccinic aciduria
• Argininemia
• Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (HHH syndrome)
• Lysinuric protein intolerance
• Citrullinemia
• N-Acetylglutamate synthase deficiency
Most of them are associated with hyperammonemia.
Urea cycle 4

Additional images

Urea cycle. Urea cycle colored.

Mnemonics
Carbombs Or Cigarettes Appear Around Fun Awesome Unique Parties
Carbombs - Carbamoyl phosphate - alcohol (Urea cycle in the liver)
Or - Ornithine/Ornithine transcarbamoylase
Cigarettes - Citrulline
Appear - Aspartate
Around - Argininosuccinate/Argininosuccinate Synthase/Argininosuccinase
Fun - Fumarate
Awesome - Arginine/Arginase
Unique - Urea
Parties - You pee in parties when you drink a lot (remember the carbombs?) and Urea is excreted in the Urine!!

External links
• The chemical logic behind the urea cycle [2]
• Basic Neurochemistry [3] - amino acid disorders

References
[1] http:/ / www. wiley. com/ college/ math/ chem/ cg/ sales/ voet. html
[2] http:/ / www2. ufp. pt/ ~pedros/ bq/ urea. htm
[3] http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=bnchm. figgrp. 3102
Article Sources and Contributors 5

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