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Urea Cycle and

Hyperammonemia
Done by
Abdulaziz massoud alfaydi
Urea
Ø The liver is the principle site of ammonia detoxification.
Ø The pathway for the detoxification of ammonia in the liver
is urea cycle, which carried out along a pathway utilizes
enzymes found in both cytosol and mitochondria
Ø High levels of ammonia in the blood are toxic, the normal
rang is (10–20 μg/dL)
Ø Nitrogen is transported between organs in organic forms
such as alanine,, glutamine, glutamate and urea.
Ø Urea is a soluble compound in water & less toxicthan
ammonia
Ø Then Urea finds its way to the kidneys to be excreted in
the urine.
Ø
Sources of Ammonia
 Many tissue particularly liver

Form ammonia from amino

acids by Transdeamination


NH3 Urea(57%)

Diet
Plasma proteins(7%)
Amino acid Body proteins(14%)
Body protein
catabolism Circulation (22%)
Sources and fat of Ammonia...
Deamintion Glutamine

Glutamate

Asparagine
Gln / Asn NH3
Pyrimidine,
Purine Pool
Urea
Putrification
Amines,
Amino Sugars
Sources of Ammonia...
Ammonia from amines:-
 Amines in diet and monoamines as hormones or
neurotransmitters give rise to ammonia by the action
of amine oxidase.

From purines and pyrimidines:-


 During catabolism of purines and
pyrimidinesammonia is removed which is formed
from the amino group attached to the purines and
pyrimidine rings.

From bacterial action in intestine:-


 Ammonia is produced by bacterial degradation of

urea in lumen of intestine and from there it is


absorbed by way of portal vein.
Transportation of
Ø There are two forms (glutamine and
ammonia
alanine) of ammonia transporter.

Ø Glutamine is a temporary nontoxic

storage it is transported to the liver

Ø kidney remove (NH3) by glutaminaseand

excreted its amide-N as ammonium


CONH2 COOH
CH2 CH2
salt (NH4+) in the urine CH2 glutaminase CH2
+ NH3
CHNH2 H2O CHNH2
COOH COOH
glutamine glutamate
Biosynthesis of Urea
Ø The Urea Cycle occurs mainly in liver

,urea excreted by kidney . Aspartate

ØThe 2 nitrogen atoms of urea enter


the Urea Cycle as NH3. and as the
amino acid (aspartate)
ØThe source of its carbon is carbon
NH2 Co2
dioxide (Co2)from respiratory .
Urea cycle
Krebs-Henseleit
Or ornithine
The enzymes catalyzing the urea cycle
reactions:
1)Carbamoyl phosphate synthetase

2)Ornithine transcarbamoylase

3)Argininosuccinate synthetase

4)Arginino succinase

5)Arginase.
Fumarate O
eturns to TCA cycle) UREA
H2N-C- NH2 2ATP + HCO3- + NH4+

Arginine Carbamoyl
 phosphate
  synthetase
Argininosuccinate Ornithine Ornithine 2ADP + Pi
AMP+PPi Carbamoyl phosphate

Citrulline
 Ornithine transcarbamoylase

Citrulline Pi
-Aspartate
ATP CYTOPLASM
-OOC-CH-NH3 + MITOCHONDRIA

CH2COO-

 argininosuccinate synthetase  argininosuccinase arginase

3ATP + HCO3- + NH4+ + aspartate  2ADP + AMP + 2Pi + PPi + fumarate + urea
Step1:
Formation of Carbamoyl Phosphate
NH 3+ CO 2
 1 mol of ammoniaand respiratory carbon
HCO3−
dioxide condense in presence of 2 ATP ATP
ADP
to form carbamoyl phosphate.
O
 This reaction catalyzed by Carbamoyl
HO C OPO32−
Phosphate Synthase (Types ǀ) . NH 3 carbonyl phosphate
Pi
 Carbamoyl Phosphate Synthase is the O
committed stepof the Urea Cycle, and H N C O

2
irreversible it is allosterically regulated. ATP
ADP carbamate
O

H 2N C OPO32−
carbamoyl phosphate
The activator N-acetylglutamate.

N-acetylglutamate
Ø Carbamoyl Phosphate Synthase has an O H
absolute requirement N-acetylglutamate is
H3C C N C COO−
an allosteric activator whose binding H
induces conformation change that CH2

enhances the affinity of the enzyme for ATP. CH2


Ø This derivative of glutamate is synthesized COO−
from acetyl-CoA & glutamate when cellular
[glutamate] is high, signaling an excess of
glutamate (Glu)
free amino acids due to protein breakdown H
or dietary intake.
H3N +
C COO−

CH2

CH2

COO
Step 2:
Formation of citrulline:-
ØCarbamoyl phosphate is transferred
to Ornithine by Ornithine
Transcarbamoylase a
mitochondrial enzyme to form Cytosol
citrulline.
Ø Citrullineleaves the mitochondria in mitochondrial matrix
exchange with ornithine which
enters from cytosol through a carbamoyl phosphate
Pi
mitochondrial inner membrane ornithine citrulline
transport system. For each cycle,
citrulline must leave the ornithine citrulline

mitochondria, and ornithine must


enter the mitochondrial matrix.
Ø An ornithine/citrulline transporter
in the inner mitochondrial
membrane facilitates
transmembrane fluxes of citrulline
& ornithine.
Step 3:
Formation of Argininosuccinate :-
Ø One molecule of aspartate is added to
citrulline forming argininosuccinate Argininosuccinate
Ø Argininosuccinate synthetase
AMP+PPi
catalyses the reaction with the
hydrolysis of ATP to AMP +PPi argininosuccinate synthetase
Citrulline
pyrophosphatasefurther splits P-P to
2 P, thus 2 high energy phosphate
-Aspartate
bonds get expended in this reaction ATP
-OOC-CH-NH3 +


CH2COO-
Step 4:
Formation of Arginine Fumarate
ØArgininosuccinate is (returns to
TCA cycle)
hydrolyzed by
argininosuccinase enzyme to
Arginine
form arginineand fumarate.

argininosuccinase

ØFumarate forms L-malate in


Argininosuccinate
TCA cycle
The Urea Cycle &TCA Cycle are
interconnected
Ø In TCA cycle Addition of H2O to
fumarate from urea cycle
forms L-malate and
subsequently NAD+
dependent oxidation of
malate forms oxaloacetate
Ø which undergoes
transaminationwith glutamate
to regenerate Aspartate.

Ø These reactions are catalyzed


by cytosolic fumarase and
malate Dehyderogenase.
Step 5 :
Formation of urea:- O
ØArginase hydrolyses arginine to urea H2N-C- NH2
and ornithine which is regenerated.
Ø
UREA

ØOrnithine re-enters mitochondria for Arginine


the operation of another urea cycle.
arginase

Ornithine
Urea Regulation
 Enzyme levels change with the protein content of diet During

starvation, activity of urea cycle enzymes are


elevatedto meet the increased rate of protein catabolism.
 High levels of glutamate leads to increased N-acetyl

glutamate and thereby enhanced activity of carbamoyl


phosphate synthase-1, thus augmenting therate of urea
synthesis
 Arginine is an activator of N-acetyl glutamate synthase.
How ammonia is toxic to CNS
1. Failure of liver function  High [NH3] would drive
Glutamine Synthase:
glutamate + ATP + NH  glutamine + ADP + P
3 i
 This would decrease glutamate which precursor for synthesis
of the neurotransmitter GABA.
2. decreased of glutamate & high ammonia level would drive

Glutamate Dehydrogenase reaction to reverse:


glutamate+NAD(P)+ α -ketoglutarate + NAD(P)H + NH +
4
 The resulting depletion of α -ketoglutarate, an essential
Krebs Cycle intermediate , impair energy metabolism in the
brain.
Types of Hyperammonemia :
Acquired :
qLiver cell failure : Liver cell cannot convert ammonia
to urea (Cirrhosis of liver due to alcoholism,
hepatitis or billiary obstruction).
qRenal failure.
qPortal blood bypasses liver and shunted directly into
systemic circulation, due to formation of collateral
circulation around liver, leading to elevated levels of
circulating ammonia.
Hereditary Hyperammonemia
 Result of Genetic deficiency of any of the Urea Cycle
enzymes leads to hyperammonemia.
 Treatment of deficiency of Urea Cycle enzymes
(depends on which enzyme is deficient):
w limiting protein intake to the amount barely adequate to
supply amino acids for growth, while adding to the diet the
α -keto acid analogs of essential amino acids.
w Liver transplantation has also been used, since liver is the
organ that carries out Urea Cycle.
Disorders Of Urea Cycle
 There are six disorders of urea cycle:
 There are deficiencies of the each of the enzymes
involved in urea cycle.
 The symptoms are due to the high levels of ammonia in
each disorder.
Symptoms of ammonia intoxication characterized by

ü Tremors,
ü Slurring of speech,
ü Blurring of vision,
ü Vomiting,
ü Irritability,
ü And hepatic coma and death
1.
1)N-Acetylglutamate synthetase
Deficiency:
Hyperammonemia and generalized

hyperaminoacidemia is noticed in a newborn whose


liver contained no detectable ability tosynthesize N-
acetyl glutamate
 Therapy administration of carbamoyl glutamate
which is an activator of carbamoyl phosphate
synthetase.
2)Hyperammonemia Type I:
 Deficiency of carbamoyl phosphate synthetase in Liver.
 Treatment supplemented with benzoate
 , phenylacetate and arginine(activator).

 3) Hyperammonemia Type II:


 x-linked inheritance. Males are affected. deficiency of
ornithine transcarbamoylase
 Orotic acid also increases because carbamoyl phosphate that
can not be used to form citrulline diffuses into the cytosol
where it condenses with aspartate becoming orotic acid and
orotic aciduriaoccurs.
4) Hypercitrullinemia :
Due to Deficiency of argininosuccinate synthetase ,

citrulline is unable to condense with aspartate to form


argininosuccinate ,and elevated levels of citrulline in
blood and urine are seen.
 5) Argininosuccinic aciduria :
Impaired ability to split argininosuccinate to form

arginine due to the deficiency of


argininosuccinase. argininosuccinate will be
accumulated
6(Hyperargininemia
Arginase deficiency is a rare disease that causes

many abnormality in the development and function


of the central nervous system.
Arginine accumulates and is excreted.

Hyperornithinemia
 Hyperammonemia syndrome:
Autosomal recessive disorder.

Elevated Ornithine and Ammonia levels in blood


due to the impaired transport of ornithine into


mitochondria via ornithine-citrulline antiporter.


Urea cycle gets impaired and ammonia levels
increase