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Urea cycle
From Wikipedia, the free encyclopedia
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), five years before the discovery of the TCA cycle.
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
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
carbamoyl phosphate + 2ADP + Pi CPS1
mitochondria
The reactions of the urea cycle
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 transcarbamoylase
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
This process requires energy, but it is necessary to convert the toxic ammonia into non-toxic urea to
transport it to the kidneys to remove the nitrogen waste. Note that reactions related to the urea cycle also
cause the production 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
toaspartate, maintaining the flow of nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 4 ATP(cytosolic NADH provides only 1.5
ATP due to the glycerol-3-phosphate shuttle who transfers the electrons from cytosolic NADH to FADH2
and that gives 1.5 ATP), a net production of one high-energy phosphate bond for the urea cycle. However,
ifgluconeogenesis 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.
Regulation
N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu,
which allosterically activates CPS1. NAcGlu is an obligate activator of Carbamoyl phosphate synthase[1].
Synthesis of NAcGlu by NAGS, is stimulated by both 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, Glu is not only a substrate for NAGS 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 ARG1do 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
the2-oxoglutarate (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
 Argininosuccinic aciduria
 Argininemia
 Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (HHH syndrome, ornithine
translocase deficiency)
 Lysinuric protein intolerance
 Citrullinemia
 N-Acetylglutamate synthase deficiency
Most of them are associated with hyperammonemia.
Additional images
Urea cycle.
Urea cycle colored.