UREA

CYCLE

INTRODUCTION

Urea is the major end product in Nitrogen

metabolism in humans and mammals.
NH3, the product of oxidative deamination reaction,
is toxic in even small amount and must be removed
from the body.
Urea cycle a.k.a Ornithine cycle is the conversion
reactions of NH3 into urea.
This reaction occur in liver (certain occur in cytosol
and mitochondria)
The urea is transported to the kidney where it is
excreted.

STEPS IN UREA
CYCLE

1.SYNTHESIS OF CARBAMOYL PHOSPHATE :

Formation of carbamoyl phosphate by

carbamoyl phoshate 1 (CPS l) is driven by the
cleavage of 2 molecules of ATP.
CPS l requires N-acetylglutamate as a positive
allosteric activator.
NH3 and CO2 incorporated into carbamoyl
phosphate, NH3 is provided primarily by the
oxidative deamination of glutamate by
mitochondrial glutamate dehydrogenase.
Nitrogen atom derived from this NH3 becomes
one of the nitrogens of urea.
This step consumes 2 ATP, and rate-limiting.

2. FORMATION OF CITRULLINE

The carbamoyl portion of carbamoyl

phosphate is transferred to ornithine by
Ornithine transcarbamoylase (OTC) as
the high-energy phosphate is released as P i .
The reactions product, citrulline, is
transported to the cytosol. citrulline produced
will transported to the cytosol by a cotransporter.

Ornithine is regenerated with each turn of

the urea cycle.

3. SYNTHESIS OF ARGININOSUCCCINATE :

Argininosuccinate synthetase combines with

citrulline with aspartate to form argininosuccinate.

The -amino group of aspartate to the second
nitrogen that is ultimately incorporated into urea.
The formation of argininosuccinate is driven by the
cleavage of ATP to AMP & pyrophosphate (PPi).
This is the third & final molecule of ATP consumed
in the formation of urea.

4. CLEAVAGE OF
ARGININOSUCCINATE :

Argininosuccinate cleaved by
argininosuccinate lyase to yield
arginine and fumarate.
The arginine formed by this reaction
serves as the immediate precursor of
urea.
Fumarate produced in the urea cycle is
hydrated to malate, -fumarate that librated here
provides a connecting link with TCA cycle and
gluconeogenesis.(see later)

5. FORMATION OF UREA :

Arginase is the final enzyme that cleaves arginine

to yield urea and ornithine.
Ornithine, so regenerated, enters mitochondria for
its reuse in the urea cycle.
Arginase is activated by Co2+ and Mn2+
Arginase is mostly found in the liver, while the rest
of the enzymes of urea cycle are also present in
other tissues.
For this reason, Arginine synthesis may occur to
varying degrees in many tissues, but only the liver
can ultimately produce urea.

OVERALL REACTION IN UREA CYCLE

The urea cycle is irreversible and consumes 4 ATP.

2 ATP are utilized for the synthesis of carbamoyl
phosphate.
1 ATP is converted to AMP and PPi to produce
arginosuccinate which equals to 2 ATP.
ATP AMP + PPi = 2 ATP equivalents

Hence 4 ATP are actually consumed.

Overall stoichiometry of the urea cycle :
Aspartate + NH3 + CO2 + 3ATP + H2O urea +
fumarate + 2ADP + AMP + 2Pi + PPi

REGULATION OF THE UREA CYCLE

N-Acetylglutamate is an essential activator for

carbamoyl phosphate synthetase Ithe rate-limiting
step in the urea cycle.
N-Acetylglutamate is synthesized from acetyl coenzyme
A and glutamate by N-acetylglutamate synthase, in a
reaction for which arginine is an activator.
Therefore, the intrahepatic concentration of Nacetylglutamate increases after ingestion of a proteinrich meal, which provides both a substrate (glutamate)
and the regulator of N-acetylglutamate synthesis.
This leads to an increased rate of urea synthesis.

SOURCES OF AMMONIA (FREE

NH3)

Glutamine-

Bacterial action in the intestine- Ammonia is formed from

The kidneys generate ammonia from glutamine by

the actions of renal glutaminase and glutamate dehydrogenase.
Ammonia is also obtained from the hydrolysis of glutamine by
intestinal glutaminase either from the blood or from digestion of
dietary protein.
urea by the action of bacterial urease in the lumen of the intestine.

Amines-

Purines and pyrimidines-

Amines obtained from the diet, and monoamines that

serve as hormones or neurotransmitters, give rise to ammonia by
the action of amine oxidase.
In the catabolism of purines and
pyrimidines, amino groups attached to the rings are released as
ammonia.

INTERRELATION BETWEEN UREA CYCLE AND TCA CYCLE

Urea cycle is linked with TCA cycle in three

different ways :
1.The production of fumarate in urea cycle is the most
important integrating point with TCA cycle. Fumarate is
converted to malate and then to OAA in TCA cycle. OAA
undergoes transamination to produce aspartate which
enters urea cycle. Here, aspartate combines with
citrulline to produce arginosuccinate. OAA is an
important metabolite which can combine with acetyl
CoA to form citrate and get finally oxidized. OAA can
also serve as a precursor for the synthesis of glucose
(gluconeogenesis).

INTERRELATION BETWEEN UREA CYCLE AND TCA CYCLE

- 4 ATP

+10 ATP

H2 O

CO2
CO2

INTERRELATION BETWEEN UREA CYCLE AND TCA

CYCLE

2.ATP (10) are generated in the TCA cycle

while ATP (4) are utilized for urea
synthesis.
3.TCA cycle is an important metabolic
pathway for the complete oxidation of
various metabolites to CO2 and H2O.
The CO2 liberated in TCA cycle (in the
mitochondria) can be used in urea
cycle.