Urea Cycle: DR Fasiha Fatima Department of Biochemistry

UREA CYCLE
DR FASIHA FATIMA
DEPARTMENT OF BIOCHEMISTRY
UREA CYCLE HISTORY
• In 1773, Rouelle isolated urea from urine

• Frederic Wohler in 1828 obtained urea by boiling an
aqueous solution of ammonium cyanate
• Urea cycle is first metabolic pathway to be elucidated in
1932
• First postulated by Henseleit Krebs
• Also called ornithine cycle because ornithine is first
member of the reaction
UREA CYCLE
“The urea cycle is a cycle of biochemical reactions occurring in
many animals that produces urea from ammonia"
PURPOSE:
• Urea is the major disposal form of amino groups and is less toxic
and very soluble than ammonia
• Urea excretion occurs through kidney
• It accounts for 90% of the nitrogen containing components of
urine
• The urea cycle is the sole source of endogenous of arginine
CHARACTERISTICS OF UREA CYCLE
SITE:
• The Urea Cycle occurs mainly in liver

• But is also occurs in kidneys and brain to some extent
• The first two reactions of urea synthesis occur in the
matrix of the mitochondria, the remaining reactions occur
in the cytosol
UREA CYCLE
SUBSTRATE:
• Ammonia (NH3) & CO2
PRODUCT:
• Urea
O
• The 2 nitrogen atoms of urea comes H 2N C NH2
from NH3 and aspartate. urea
• Carbon atom comes from CO2
STEPS OF UREA CYCLE
STEP 1: FORMATION OF CARBOMYL PHOSPHATE
2ATP 2ADP + Pi
O
NH3 + HCO3 – H 2N C OP
Carbamyl Phosphate
Reaction is catalyzed by carbomyl phosphate synthetase I (CPS-I)
Rate limiting step
CPS-I (Mitochondria) Uses NH3
CPS-II (Cytosol) Uses Glutamine and used in pyrimidine biosynthesis
STEPS OF UREA CYCLE
STEP 2: FORMATION OF CITRULLINE
Citrulline leaves the mitochondria and further reactions take

place in cytoplasm
STEPS OF UREA CYCLE
STEP 3: FORMATION OF ARGININOSUCCINATE

• Condensation of citrulline with aspartate to form arginosuccinate
• ATP are required
H2C COO –
H
O NH2 H2N N C COO –
C C
H
NH ATP AMP + PP i NH
(CH 2) 3 H2C COO – (CH 2) 3
+H N
3 C COO – + +H N
3 C COO – +H N
3 C COO –
H H H
Citrulline As partate Argininosuccinate
Argininosuccinate synthetase catalyzes the reaction

STEPS OF UREA CYCLE
STEP 4: FORMATION OF ARGININE AND FUMARATE
Arginosuccinase cleaves arginosuccinate to form arginine and

fumarate
STEPS OF UREA CYCLE
STEP 5: FORMATION OF UREA
Arginase-I catalyzed the reaction. The arginine is hydrolyzed to

produce the urea and to reform the ornithine. The ornithine re-
enters the mitochondrial matrix.
STEPS OF UREA CYCLE
• Arginase-I is exclusively found in liver
• Ornithine and lysine are potent inhibitors of arginase and compete
with arginine
• In kidneys arginine can synthesized from citrulline
• Arginine –II in kidneys control arginine availability for nitric oxide
synthesis
• Arginine is also serve as precursor of potent muscle relaxant nitric
oxide (NO)
ENERGETICS OF UREA CYCLE
NH3 + CO2 + Aspartate + 4 ATP  urea + fumarate

ENERGY UTILISED:
• 2 ATPs during formation of Carbamoyl Phosphate
• 2 ATP during formation of argininosuccinte
• Fumarate converted into malate in TCA and produced 1
NADH which is equivalent to 2.5 ATP
• So the net energy utilized is 1.5 ATP.
REGULATION OF UREA CYCLE
1. COARSE REGULATION:
• Dietary intake is primarily proteins  much urea (amino acids are
used for fuel)
• Prolonged starvation  breaks down of muscle proteins  Activity of
urea cycle increased
2. FINE REGULATION:
• Carbamoyl phosphate synthetase I is allosterically activated by N-
acetylglutamate.
• N-acetylglutamate is synthesized from glutamate and acetyl-CoA by
N-acetylglutamate synthase, it is hydrolyzed by a specific
hydrolase.
• Rate of urea production is dependent on [N-acetylglutamate].
• Excess Glutamate causes an increase in N-acetylglutamate which
stimulates CPS I causing increases in urea cycle.
FATE OF UREA
• Urea formed in the liver is transported through circulation to
kidneys for excretion through urine
• A portion of urea diffuses from the blood into the intestine and is
cleaved to CO2 and ammonia by bacterial enzyme urease
(ammonia is partly lost in feces and partly reabsorbed)
• In chronic renal failure elevated urea levels leads to
hyperammonemia
• Oral administration of antibiotics also reduces the no. of intestinal
bacterial flora
• Normal urea level in plasma is 20-40 mg/dl
• Urinary excretion of urea is 15-30 g/day.
Linked to Citric Acid Cycle
• The urea cycle is linked to the citric acid cycle: Kreb’s
Bi-cycle or urea bicycle!!
20
DISORDERS OF UREA CYCLE
• Enzyme deficiency results in hyperammonemia
• When block is in earlier steps, the condition is more severe since
ammonia itself accumulates.
• Deficiency in later enzymes results in accumulation of other
metabolites which less toxic
• Hyperammonemia, encephalopathy and respiratory alkalosis
• Symptoms:
• Vomiting, lethargy, irritability, lethargy and severe mental retardation
HYPERAMMONEMIA
• Genetic deficiencies of each of

CONGENITAL five enzymes of urea cycle
• Viral hepatitis
ACQUIRED • Alcohol
• Cirrhosis
HYPERAMMONEMIA TYPE I
Carbamoyl Phosphate synthetase (CPS-1) deficiency

• Deficiency of CPS-I is the most severe of the urea cycle
disorders
• Individuals with complete CPS-I deficiency rapidly develop
hyperammonemia in the newborn period
• Children who are successfully rescued from crisis are
chronically at risk for repeated bouts of hyperammonemia
HYPERAMMONEMIA TYPE II
• Ornithine Transcarbamoylase deficiency (OTC deficiency)
• The disease is characterized as X linked dominant
• The disease is much more severe in males than in females.
FEATURES
• Increased ammonia & orotic acid in blood
• Increased glutamine in blood, CSF and urine
• Orotic aciduria: Due to channeling of carbomyl phosphate into
pyrimidine synthesis.
HYPERORNITHINEMIA
• Defective ornithine transporter protein

• The failure to import cytosolic ornithine into the
mitochondrial matrix
• Hyperammonemia, homocitrullinuria and the
accompanying accumulation of cytosolic ornithine
results in Hyperornithinemia (HHH Syndrome)
• Decreased urea in blood
CITRUNLLINEMIA
• Argininosuccinate synthetase deficiency
• Autosomal recessive inheritance
• High blood levels of ammonia and citrulline
• High levels of citrulline in urine (1-2 g/day)
• CSF citrulline levels are also elevated
ARGININOSUCCINIC ACIDURIA
• Argininosuccinase or argininosuccinate lyase deficiency
• A rare disease characterized by elevated levels of argininosuccinate in
blood, cerebrospinal fluid, and urine is associated with friable, tufted
hair (trichorrhexis nodosa)
• Autosomal recessive inheritance
• Diagnosis by measurement of erythrocyte
argininosuccinase activity can be performed on
umbilical cord blood or amniotic fluid cells
HYPERARGININEMIA
• Arginase deficiency
• Autosomal recessive disorder
• First symptoms of hyperargininemia typically do not appear
until age of 2-4 years
• Elevated blood and cerebrospinal fluid arginine levels, low
erythrocyte levels of arginase
TREATMENT
• Restriction of dietary
proteins
• Administration of
compounds that binds
covalently to non-essential
amino acids e.g.
phenylbutyrate given orally
is converted to
phyenlacetate which
condenses with glutamine
TANDEM MASS SPECTRMETERY CAN
DETECT METABOLIC DISEASES

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UREA CYCLE

• In 1773, Rouelle isolated urea from urine

• The Urea Cycle occurs mainly in liver

Citrulline leaves the mitochondria and further reactions take

STEP 3: FORMATION OF ARGININOSUCCINATE

Citrulline As partate Argininosuccinate

Argininosuccinate synthetase catalyzes the reaction

Arginosuccinase cleaves arginosuccinate to form arginine and

Arginase-I catalyzed the reaction. The arginine is hydrolyzed to

NH3 + CO2 + Aspartate + 4 ATP  urea + fumarate

• Genetic deficiencies of each of

Carbamoyl Phosphate synthetase (CPS-1) deficiency

• Defective ornithine transporter protein

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