Urea Cycle

UREA CYCLE
An Overview on the Biosynthesis of UREA
Gowtham Arvind
1st Year MBBS
Biosynthesis of Urea
Urea is the major end product of Nitrogen catabolism in Humans
Urea synthesis is a cyclic process.

The major metabolic role of ornithine, citrulline, and argininosuccinate in
mammals is urea synthesis.
Some reactions of urea synthesis occur in the matrix of the mitochondrion, and
other reactions in the cytosol.
Urea synthesis is a cyclic process. While ammonium ion, CO2, ATP, and
aspartate are consumed, the ornithine consumed in reaction 2 is regenerated in
reaction 5. Thus, there is no net loss or gain of ornithine, citrulline,
argininosuccinate, or arginine.
The two nitrogen atoms of urea are derived from two different sources, one from
ammonia and the other directly from the alpha amino group of aspartic acid.
Introduction to Urea cycle
What led to the discovery of Urea cycle?
In 1773, Rouelle isolated urea from urine.

In 1828, Fredric Wohler obtained urea by boiling an aqueous solution of ammonium
cyanate.
In 1932, The urea cycle is the first metabolic pathway to be elucidated by Hans
Krebs (1900– 1981) and Kurt Henseleit (1907–1972).
Hence, the cycle is known as Krebs-Henseleit urea cycle.
As ornithine is the first member of the reaction, it is also called as Ornithine cycle.
Introduction to Urea Cycle
Why Urea?
Urea is the major disposal form of amino groups derived from amino acids, and
accounts for about 90% of the nitrogen-containing components of urine.
One nitrogen of the urea molecule is supplied by free ammonia, and the other
nitrogen by aspartate.
[Note: Glutamate is the immediate precursor of both ammonia (through oxidative deamination by glutamate dehydrogenase) and aspartate nitrogen (through transamination of
oxaloacetate by AST).]
The carbon and oxygen of urea are derived from CO2.

Urea is produced by the liver, and then is transported in the blood to the kidneys for
excretion in the urine.
REACTIONS OF CYCLE
The first two reactions leading to the synthesis of urea occur
in the mitochondria, whereas the remaining cycle enzymes
are located in the cytosol
STEP 1 : Carbamoyl Phosphate Synthetase I Initiates Urea
Biosynthesis
Formation of Carbomyl Phosphate
Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed

by mitochondrial carbamoyl phosphate synthetase-I (CPS-I) (EC 6.3.4.16).
Synthesis of 1 mol of carbamoyl phosphate requires 2 mol of ATP. (Note: ATP serves as the
phosphoryl donor for formation of the mixed acid anhydride bond of carbamoyl phosphate. The second ATP provides the driving force for
synthesis of the amide bond of carbamoyl phosphate.)
Phosphorylation of carbamate by the second ATP then forms carbamoyl phosphate.

Carbamoyl Phosphate Synthetase I Is the Pacemaker Enzyme of the Urea Cycle
CPS-I reaction is the rate-limiting step in urea formation. It is
irreversible and is active only in the presence of N-acetylglutamate,
an allosteric activator that enhances the affinity of the synthetase for
ATP.
STEP 2: Carbamoyl Phosphate Plus Ornithine Forms Citrulline
Formation of Citrulline
L-Ornithine transcarbamoylase (EC 2.1.3.3) catalyzes transfer of the carbamoyl

group of carbamoyl phosphate to ornithine as the high-energy phosphate is released as
Pi , forming citrulline and orthophosphate.
[Note: Ornithine and citrulline are basic amino acids that participate in the urea cycle, moving across the inner mitochondrial membrane via a cotransporter. They are not
incorporated into cellular proteins because there are no codons for these amino acids]
Ornithine is regenerated with each turn of the urea cycle, much in the same way that
oxaloacetate is regenerated by the reactions of the citric acid cycle.
Entry of ornithine into mitochondria and exodus of citrulline from mitochondria
therefore involve mitochondrial inner membrane permeases. Thus, The citrulline
leaves the mitochondria and further reactions are taking place in cytoplasm.
Citrulline is neither present in blood nor in tissue, it is present in milk.
STEP 3: Citrulline Plus Aspartate Forms Argininosuccinate
Synthesis of Argininosuccinate
Argininosuccinate synthetase (EC 6.3.4.5) links aspartate and citrulline via the
amino group of aspartate and provides the second nitrogen of urea.
The reaction requires ATP and involves intermediate formation of citrullyl-AMP.
Subsequent displacement of AMP by aspartate then forms argininosuccinate.
This is the third and final molecule of ATP consumed in the formation of urea.
The α-amino group of aspartate provides the second nitrogen that is ultimately
incorporated into urea.
STEP 4: Cleavage of Argininosuccinate Forms Arginine &
Fumarate
Formation of Arginine
Argininosuccinate is cleaved by argininosuccinate lyase to yield arginine and

fumarate.
The arginine formed by this reaction serves as the immediate precursor of urea.
The enzyme is inhibited by fumarate. But this is avoided by the cytoplasmic
localization of the enzyme.
The fumarate formed may be funnelled into TCA cycle to be converted to malate and
then to oxaloacetate to be transaminated to aspartate. Thus the urea cycle is linked to
TCA cycle through fumarate.
The 3rd and 4th steps taken together may be summarised as:
Citrulline + aspartate → Arginine + fumarate
STEP 5: Cleavage of Arginine Releases Urea & Reforms
Ornithine
Formation of Urea
Hydrolytic cleavage of the guanidino group of arginine, catalyzed by liver arginase

(EC 3.5.3.1), releases urea.
Only the liver can cleave arginine and, thereby, synthesize urea.
The other product, ornithine, reenters liver mitochondria and participates in
additional rounds of urea synthesis.
Thus, ornithine may be considered as a catalyst which enters the reaction and is
regenerated.
Ornithine and lysine are potent inhibitors of arginase, and compete with arginine.
STEP 6:
Fate of Urea
Urea diffuses from the liver, and is transported in the blood to the kidneys, where it
is filtered and excreted in the urine.
A portion of the urea diffuses from the blood into the intestine, and is cleaved to CO
2and NH by bacterial urease.
3
This ammonia is partly lost in the feces, and is partly reabsorbed into the blood.
Summary of Urea cycle
Flow of Nitrogen to
form Urea
Role of Ornithine
Ornithine may be considered as a catalyst which enters the reaction and is

regenerated.
The major role of ornithine is in urea cycle which enters the cycle and regenerated at
the end of the cycle. None of the atoms of ornithine is incorporated into urea.
Ornithine only acts as the precursor of arginine and citrulline. It is not used for
protein synthesis.
Role of Ornithine
Ornithine is used for the synthesis of polyamines after decarboxylation. The enzyme
is ornithine decarboxylase (ODC).
Ornithine ——-ODC-——> Putrescine + CO2
Putrescine combines with propylamine derived from methionine to form
spermidine.
Addition of another propylamine will give rise to spermine.
The propylamine is donated by Ado-Met leaving behind methylthioadenosine,
which can be used to resynthesize methionine.
ENERGETICS OF CYCLE
The overall reaction may be summarized as:NH3 + CO2 +
Aspartate → Urea + Fumarate
Energetics of Urea cycle
NH3 + CO2 + Aspartate → Urea + Fumarate
In the urea cycle 2 ATPs are used in the first reaction.

Another ATP is converted to AMP and PPi,which is equivalent to 2 ATPs.The urea
cycle consumes 4 high energy phosphate bonds.
However, fumarate formed in the 4th step may be converted to malate. Malate when
oxidized to oxaloacetate produces 1 NADH equivalent to 2.5 ATP.
So, net energy expenditure is only 1.5 high energy phosphates. The urea cycle and
TCA cycle are interlinked, and so, it is called as "urea bicycle".
Thank you for your patience!

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An Overview on the Biosynthesis of UREA

Urea synthesis is a cyclic process.

In 1773, Rouelle isolated urea from urine.

The carbon and oxygen of urea are derived from CO2.

Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed

Phosphorylation of carbamate by the second ATP then forms carbamoyl phosphate.

L-Ornithine transcarbamoylase (EC 2.1.3.3) catalyzes transfer of the carbamoyl

Argininosuccinate is cleaved by argininosuccinate lyase to yield arginine and

Hydrolytic cleavage of the guanidino group of arginine, catalyzed by liver arginase

Ornithine may be considered as a catalyst which enters the reaction and is

In the urea cycle 2 ATPs are used in the first reaction.

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