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Done by Abdulaziz massoud alfaydi
Urea Cycle and Hyperammonemia
UreaThe liver is the principle site of ammonia detoxification.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
High levels of ammonia in the blood are toxic, the normal rang is (10–20 μg/dL)
Nitrogen is transported between organs in organic forms such as alanine,, glutamine, glutamate and urea.
Urea is a soluble compound in water & less toxic than ammonia
Then Urea finds its way to the kidneys to be excreted in the urine.
Many tissue particularly liver
Form ammonia from amino
acids by Transdeamination
Sources of Ammonia
Amino acid
Diet
Body protein catabolism
NH3 Urea(57%)
Plasma proteins(7%)
Body proteins(14%)
Circulation (22%)
Sources and fat of Ammonia...
NH3
Pool
Glutamine
Asparagine
Urea
Glutamate
Deamintion
Amines,Amino Sugars
Pyrimidine, Purine
Gln / Asn
Putrification
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 pyrimidines
ammonia 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 ammoniaThere are two forms (glutamine and
alanine) of ammonia transporter.
Glutamine is a temporary nontoxic
storage it is transported to the liver
kidney remove (NH3) by glutaminase
and excreted its amide-N as ammonium
salt (NH4+) in the urine
CONH2
CH2
CH2
CHNH2
COOHglutamine
COOH
CH2
CH2
CHNH2
COOHglutamate
H2O+ NH3
glutaminase
The Urea Cycle occurs mainly in
liver ,urea excreted by kidney .
The 2 nitrogen atoms of urea enter
the Urea Cycle as NH3.and as the
amino acid (aspartate)
The source of its carbon is carbon
dioxide (Co2) from respiratory .
Biosynthesis of Urea
Co2
Aspartate
NH2
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.
3ATP + HCO3- + NH4
+ + aspartate 2ADP + AMP + 2Pi + PPi + fumarate + urea
CYTOPLASM MITOCHONDRIA
Ornithine
Citrulline
argininosuccinate synthetase argininosuccinase arginase
AMP+PPi
-Aspartate
Argininosuccinate
ATP
Arginine
Fumarate(returns
to TCA cycle)
Pi
Ornithine
Citrulline
Ornithine transcarbamoylase
Carbamoyl phosphate
2ATP + HCO3- + NH4
+
2ADP + Pi
Carbamoyl phosphate synthetase
O
H2N-C- NH2
UREA
Ornithine
-OOC-CH-NH3+
CH2COO-
1 mol of ammonia and respiratory
carbon dioxide condense in presence of
2 ATP to form carbamoyl phosphate.
This reaction catalyzed by Carbamoyl
Phosphate Synthase (Types ǀ) .
Carbamoyl Phosphate Synthase is the
committed step of the Urea Cycle, and
irreversible it is allosterically regulated.
NH3+ CO2
H2N C OPO32
O
H2N C O
O
HO C
O
OPO32
HCO3
ATP
NH3
ADP ATP
Pi
ADP
carbonyl phosphate
carbamate
carbamoyl phosphate
Step1: Formation of Carbamoyl Phosphate
The activator N-acetylglutamate.
Carbamoyl Phosphate Synthase has an
absolute requirement N-acetylglutamate is
an allosteric activator whose binding
induces conformation change that
enhances the affinity of the enzyme for ATP.
This derivative of glutamate is synthesized
from acetyl-CoA & glutamate when cellular
[glutamate] is high, signaling an excess of
free amino acids due to protein breakdown
or dietary intake.
NH
C COO
CH2
CH2
COO
H
CH3C
O
N-acetylglutamate
H3N+ C COO
CH2
CH2
COO
H
glutamate (Glu)
Step 2: Formation of citrulline-:
Carbamoyl phosphate is transferred to Ornithine by Ornithine Transcarbamoylase a mitochondrial enzyme to form citrulline.
Citrulline leaves the mitochondria in exchange with ornithine which enters from cytosol through a mitochondrial inner membrane transport system. For each cycle, citrulline must leave the mitochondria, and ornithine must enter the mitochondrial matrix.
An ornithine/citrulline transporter in the inner mitochondrial membrane facilitates transmembrane fluxes of citrulline & ornithine.
Cytosol
mitochondrial matrix
carbamoyl phosphate Pi
ornithine citrulline
ornithine citrulline
Step 3:Formation of Argininosuccinate-:
One molecule of aspartate is added
to citrulline forming
argininosuccinate
Argininosuccinate synthetase
catalyses the reaction with the
hydrolysis of ATP to AMP +PPi
pyrophosphatase further splits P-P
to 2 P, thus 2 high energy phosphate
bonds get expended in this reaction
Citrulline
AMP+PPi
-Aspartate
Argininosuccinate
ATP-OOC-CH-NH3
+
CH2COO-
argininosuccinate synthetase
Step 4: Formation of Arginine
Argininosuccinate is
hydrolyzed by
argininosuccinase enzyme to
form arginine and fumarate.
Fumarate forms L-malate in
TCA cycle
Argininosuccinate
Arginine
Fumarate
(returns to TCA cycle)
argininosuccinase
The Urea Cycle &TCA Cycle are interconnected
In TCA cycle Addition of H2O to fumarate from urea cycle forms L-malate and subsequently NAD+ dependent oxidation of malate forms oxaloacetate
which undergoes transamination with glutamate to regenerate Aspartate.
These reactions are catalyzed by cytosolic fumarase and malate Dehyderogenase.
Step 5 : Formation of urea-:
Arginase hydrolyses arginine to
urea and ornithine which is
regenerated.
Ornithine re-enters mitochondria for
the operation of another urea cycle.
Arginine
O
H2N-C- NH2
UREA
Ornithine
arginase
Urea Regulation
Enzyme levels change with the protein content of diet
During starvation, activity of urea cycle enzymes are
elevated to 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 the rate 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 + NH3 glutamine + ADP + Pi
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)+ a-ketoglutarate + NAD(P)H + NH4+
The resulting depletion of a-ketoglutarate, an essential
Krebs Cycle intermediate , impair energy metabolism in the
brain.
Types of Hyperammonemia :Acquired :
Liver cell failure : Liver cell cannot convert
ammonia to urea (Cirrhosis of liver due to
alcoholism, hepatitis or billiary obstruction).
Renal failure.
Portal 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):
limiting protein intake to the amount barely adequate to
supply amino acids for growth, while adding to the diet the a-
keto acid analogs of essential amino acids.
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
Tremors, Slurring of speech, Blurring of vision, Vomiting, Irritability,And hepatic coma and death
1) N-Acetylglutamate synthetase Deficiency:
Hyperammonemia and generalized
hyperaminoacidemia is noticed in a newborn whose
liver contained no detectable ability to synthesize
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
aciduria occurs.
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
Thank you
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