The urea cycle converts toxic ammonium ions produced during amino acid degradation into urea in the liver. There are four reactions that make up the urea cycle: 1) Formation of carbamoyl phosphate from ammonia in the mitochondria 2) Transfer of carbamoyl group to ornithine to form citrulline in the mitochondria 3) Condensation of citrulline and aspartate to form argininosuccinate in the cytosol 4) Hydrolysis of arginine to urea and ornithine in the cytosol. The urea is then released from the liver and excreted in urine. Problems with the urea cycle can cause a toxic buildup of ammon

1. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
The Urea Cycle

2. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Urea Cycle
The ammonium ion, the end product of amino acid
degradation, is toxic if it is allowed to accumulate. The urea
cycle converts ammonium ions to urea, which is transported
to the kidneys to form urine.
Learning Goal Describe the formation of urea from an
ammonium ion.

3. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Urea Cycle
The urea cycle in the liver cells
• consists of reactions that occur in the mitochondria and
cytosol.
• detoxifies ammonium ions from amino acid degradation.
• begins with the conversion of ammonium ions to carbamoyl
phosphate using energy from two ATP.

4. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Reaction 1: Transfer, Carbamoyl Group
Reaction 1 of the urea cycle occurs in the mitochondrial
matrix, where
• ornithine transcarbamylase catalyzes transfer of the
carbamoyl group from carbamoyl phosphate to ornithine.
• the reaction yields citrulline, which is transported across the
mitochondrial membrane by the citrulline transporter into the
cytosol.
• hydrolysis of the high-energy phosphate bond in carbamoyl
phosphate provides the energy to drive the reaction.

5. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Reaction 1: Transfer, Carbamoyl Group

6. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Reaction 2: Condensation with Aspartate
Reaction 2 of the urea cycle
occurs in the cytosol, where
• argininosuccinate
synthetase catalyzes the
condensation of citrulline
with aspartate, producing
argininosuccinate.
• the hydrolysis of two
phosphate bonds in ATP
to yield AMP and two
inorganic phosphates
provides energy for the
reaction.

7. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Reaction 3: Cleavage of Fumarate
Reaction 3 of the urea cycle
occurs in the cytosol, where
• argininosuccinate lyase
splits argininosuccinate.
• the products are arginine
and fumarate, a citric acid
cycle intermediate.

8. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Reaction 4: Hydrolysis of Arginine
Reaction 4 of the urea cycle
occurs in the cytosol, where
• arginase catalyzes the
hydrolysis of arginine.
• the products are urea and
ornithine.
Ornithine returns to the
mitochondrial matrix to
repeat the urea cycle.

9. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Urea Cycle, Overview

10. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Study Check
Identify the site for each as either mitochondrion or cytosol.
A. formation of urea
B. formation of carbamoyl phosphate
C. combination of aspartate with citrulline
D. cleavage of fumarate
E. formation of citrulline

11. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
Solution
Identify the site for each as either mitochondrion or cytosol.
A. formation of urea cytosol
B. formation of carbamoyl phosphate mitochondrion
C. combination of aspartate with citrulline cytosol
D. cleavage of fumarate cytosol
E. formation of citrulline mitochondrion

12. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• If there is a problem with the urea
cycle, then the level of ammonia in
the blood will rise, causing
hyperammonemia
• Ammonia is able to cross the barrier
between the bloodstream and the
brain

13. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• Once it enters the brain, it can stop
the TCA cycle by depleting one of the
metabolites, α-ketoglutarate
• This means that these brain cells
cannot make energy, ultimately
leading to its death.

14. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• This eventually will lead to
neurological problems, which can be
as severe as irreversible brain
damage.
• Problems can be caused by things
such as damage to the liver
(cirrhosis) or by an inherited defect in
one of the above enzymes.

15. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• In both cases, the level of ammonia
rises with the potential consequences
listed above.
• Inherited urea cycle defects are part
of “inborn errors in metabolism”, and
are known as “urea cycle disorders”

16. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• This eventually will lead to
neurological problems, which can be
as severe as irreversible brain
damage.
• Symptoms usually present in
newborns around 24-48 hours after
birth. The most severe symptoms are
seen in newborns with a defect in
CPS.

17. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• Treatment for hyperammonemia
consists of removing protein from the
diet, removing the excess ammonia
and supplementing with molecules of
the urea cycle which are missing.
• Also, sodium benzoate and sodium
acetate can be used to form
ammonia-containing compounds
which can be excreted through feces.

18. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• Treatment for hyperammonemia
consists of removing protein from
the diet, removing the excess
ammonia and supplementing with
molecules of the urea cycle which
are missing.

19. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• Also, sodium benzoate and sodium
acetate can be used to form
ammonia-containing compounds
which can be excreted through feces.
• The sugar lactulose was shown to
reduce the production of ammonia by
the gut bacteria, as well as promoting
the excretion of ammonia through
feces

20. General, Organic, and Biological Chemistry: Structures of Life, 5/e
Karen C. Timberlake
© 2016 Pearson Education, Inc.
What Happens when it things Wrong?
• Alternatively, antibiotics can be
used to eliminate the ammonia-
forming gut bacteria.
The End