The synthesis of carbamoyl phosphate and the urea cycle are

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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.
1 Function
2 Reactions
3 Regulation
o 3.1 N-Acetylglutamic acid
o 3.2 Substrate concentrations
4 Pathology
5 Additional images
6 References
7 External links
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.
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 "highenergy" 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
1 NH4+ + HCO3− + 2ATP
2 carbamoyl phosphate +
carbamoyl phosphate +
2ADP + Pi
citrulline + Pi
citrulline + aspartate +
argininosuccinate + AMP +
Arg + fumarate
4 argininosuccinate
ornithine + urea
5 Arg + H2O
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 +
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 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 to aspartate,
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, 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.
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 elevated when free amino acids are
elevated. So Glu not only is 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 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 intellectual disability and lethargy). This
clearing system involves GLUD1 and GLUL, which decrease the 2-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)
Deficiencies of the various enzymes and transporters involved in the urea cycle can
cause urea cycle disorders:
N-Acetylglutamate synthase deficiency
Carbamoyl phosphate synthetase deficiency
Ornithine transcarbamoylase deficiency
Citrullinemia (Deficiency of argininosuccinic acid synthase)
Argininosuccinic aciduria (Deficiency of argininosuccinic acid lyase)
Argininemia (Deficiency of arginase)
Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (Deficiency
of the mitochondrial ornithine transporter)
Most urea cycle disorders are associated with hyperammonemia, however argininemia
and some forms of argininosuccinic aciduria do not present with elevated ammonia