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The Urea Cycle: Eliminate Ammonium Ion Via The Urea Cycle. Urea Is Excreted in The Urine

The urea cycle consists of 5 enzyme-catalyzed steps that convert excess ammonia produced during amino acid catabolism into urea for excretion. Step 1 involves carbamoyl phosphate synthetase converting ammonia and bicarbonate into carbamoyl phosphate. Step 2 transfers the carbamoyl group to ornithine. Step 3 adds aspartate to form argininosuccinate. Step 4 splits this into fumarate and arginine. Step 5 hydrolyzes arginine into urea and ornithine to complete the cycle. Failure of urea cycle enzymes can cause toxic hyperammonemia.

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0% found this document useful (0 votes)
35 views13 pages

The Urea Cycle: Eliminate Ammonium Ion Via The Urea Cycle. Urea Is Excreted in The Urine

The urea cycle consists of 5 enzyme-catalyzed steps that convert excess ammonia produced during amino acid catabolism into urea for excretion. Step 1 involves carbamoyl phosphate synthetase converting ammonia and bicarbonate into carbamoyl phosphate. Step 2 transfers the carbamoyl group to ornithine. Step 3 adds aspartate to form argininosuccinate. Step 4 splits this into fumarate and arginine. Step 5 hydrolyzes arginine into urea and ornithine to complete the cycle. Failure of urea cycle enzymes can cause toxic hyperammonemia.

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karam ali
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The Urea Cycle

Oxidative deamination of glutamate in


mitochondria produces large amounts of
ammonium ion
Glutamate + H2O -ketoglutarate + NH3

As ammonium ion is toxic it must be removed


quickly from the body regardless of the energy
required
Eliminate ammonium ion via the urea cycle. Urea is
excreted in the urine
Failure of enzymes in the urea cycle can be genetic
and leads to hyperammonemia
Severe cases lead to early death from toxic ammonium
ion buildup
Schematic of the Urea Cycle
Step 1
First step combines CO2 and NH4+ to form
The Urea Cycle

carbamoyl phosphate
Reaction requires ATP and H2O
Takes place in the mitochondria
Catalyzed by carbamoyl phosphate synthase
Step 2
Carbamoyl phosphate condenses with the
amino acid ornithine to produce the amino acid
The Urea Cycle

citrulline
Occurs in the mitochondria
Catalyzed by ornithine transcarbamoylase
Step 3
Citrulline is transported to the cytoplasm
Condenses with aspartate to produce
The Urea Cycle

argininosuccinate
Catalyzed by argininosuccinate synthase
Requires energy released by ATP hydrolysis
Step 4
Argininosuccinate cleaved to produce the
amino acid arginine and fumarate of the citric
The Urea Cycle

acid cycle
Reaction catalyzed by argininosuccinate lyase
Step 5
Final reaction hydrolyzes arginine to generate
urea the reaction product that is excreted
The Urea Cycle

Reaction also regenerates ornithine, the original


reactant in the cycle
Reaction is catalyzed by arginase
Regulation of the urea cycle
Carbamoyl phosphate synthetase I is 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].
When aa breakdown rates increase, excess nitrogen must be
excreted. This results in increase in Glu through
transamination reactions.
Excess Glu causes an increase in N-acetylglutamate which
stimulates CPS I causing increases in urea cycle.
Carbamoyl phosphate synthetase
Carbamoyl phosphate synthetase (CPS) catalyzes the
condensation and activation NH3 and HCO3- to form carbomyl
phosphate (first nitrogen containing substrate).
Uses 2 ATPs.
O

2ATP + NH3 + HCO3- NH2-C-OPO3- + 2ADP + 2Pi


Carbamoyl phosphate

Eukaryotes have 2 types of CPS enzymes


1. Mitochondrial CPSI uses NH3 as its nitrogen donor and participates in urea
biosynthesis.
2. Cytosolic CPSII uses glutamine as its nitrogen donor and is involved in
pyrimidine biosynthesis.
Ornithine transcarbomylase
Transfers the carbomoyl group of carbomyl phosphate to ornithine
to make citrulline
Reaction occurs in mitochondrion.
Ornithine produced in the cytosol enters via a specific transport
system.
Citrulline is exported from the mitochondria.
Arginocuccinate Synthetase
2nd N in urea is incorporated in the 3rd reaction of the urea cycle.
Condensation reaction with citrullines ureido group with an Asp
amino group catalyzed by arginosuccinate synthetase.
Ureido oxygen is activated as a leaving group through the
formation of a citrulyl-AMP intermediate.
This is displaced by the Asp amino group to form
arginosuccinate.
Arigininosuccinase and Arginase
Argininosuccinse catalyzes the elimination of Arg from
the the Asp carbon skeleton to form fumurate.
Arginine is the immediate precursor to urea.
Fumurate is converted by fumarase and malate
dehydrogenase.

Arginase catalyzes the fifth and final reaction of the


urea cycle.
Arginine is hydrolyzed to form urea and regenerate
ornithine.
Ornithine is returned to the mitochondria.
1. Carbamoyl
phosphate
synthetase (CPS)
2. Ornithine
transcarbamoylase
3. Argininosuccinate
synthetase
4. Arginosuccinase
5. Arginase
Page 992

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