Urea Cycle4

Lecture 4: Protein and Amino acid Metabolism by Dr. Sura A.
Abdulsattar (2021-2022)
Urea Formation (Krebs-Henseleit cycle)

Ammonia is highly toxic to the central nervous system. It is converted to urea, which
is much less toxic, water soluble and easily excreted in urine. The liver is the site of
Urea biosynthesis. Urea biosynthesis occurs by urea cycle (Krebs Henseleit cycle in
five steps. The first 2 steps occur in mitochondria, while the last 3 steps occur in
cytoplasm. It is catalyzed by five enzymes. Any defect in one of these enzymes leads
to ammonia intoxication. The two nitrogen atoms of urea are derived from two
different sources, one from ammonia and the other directly from the alpha amino
group of aspartic acid.
Note
Other Organs
• Kidneys: Urea cycle operates in a limited extent. Kidney can form up to arginine
but cannot form urea,
as enzyme arginase is absent in kidney tissues.
• Brain: Brain can synthesis urea from citrulline, but lacks the enzyme for forming
citrulline from ornithine.
Thus, neither the kidneys nor the brain can form urea in significant amounts.
Steps of urea biosynthesis

1- Biosynthesis of carbamoyl phosphate
One molecule of ammonia condenses with CO2 in the presence of two molecules
of ATP to form carbamoyl phosphate. The reaction is catalyzed by the mitochondrial
enzyme carbamoyl phosphate synthetase-I
1
Lecture 4: Protein and Amino acid Metabolism by Dr. Sura A. Abdulsattar (2021-2022)
2- Formation of citrulline
The second reaction is also mitochondrial. The carbamoyl group is transferred to
the NH2 group of ornithine by ornithine transcarbamoylase .
3-Formation of argininosuccinate
One molecule of aspartic acid adds to citrulline forming a carbon to nitrogen bond,
which provides the 2nd nitrogen atom of urea. Argininosuccinate synthetase
catalyzes the reaction. This needs hydrolysis of ATP to AMP level, so two high
energy phosphate bonds are utilized. The PPi is an inhibitor of this step.
4-Cleavage of argininosuccinate
Argininosuccinate is cleaved by argininosuccinate lyase (argininosuccinase) to
arginine and fumarate . Fumarate produced is used to regenerate aspartic acid
again.
2
5- Cleavage of arginine
The final reaction of the cycle is the hydrolysis of arginine to urea and ornithine by
arginase.
3
Biosynthesis of urea or ornithine—urea cycle
4
Regulation of urea cycle

The major regulatory step is catalyzed by CPS-I where the positive effector is N-
acetyl glutamate (NAG). It is formed from glutamate and acetyl CoA . Arginine is
an activator of NAG synthase.
Disorders of Urea Cycle

Deficiency of any of the urea cycle enzymes would result in hyperammonemia.
When the block is in one of the earlier steps, the condition is more severe, since
ammonia itself accumulates. Deficiencies of later enzymes result in the
accumulation of other intermediates, which are less toxic and hence symptoms are
less. As a general description, disorders of urea cycle is characterized by
hyperammonemia, encephalopathy and respiratory alkalosis. Clinical symptoms
include vomiting, irritability, lethargy and severe mental retardation. Infants appear
normal at birth, but within days progressive lethargy.
Clinical significance of urea:

1-Normal level: the normal concentration of blood plasma in healthy adult ranges
from 20-40 mg/dl
2- Increase levels Increases in blood urea may occur in a number of diseases in
addition to those in which the kidneys are primarily involved. The causes can be
classified as:
• Prerenal,
• Renal, and
• Postrenal
(a) Prerenal
most important are conditions in which plasma vol / body-fluid are reduced:
5
• Salt and water depletion,

• Severe and protracted vomiting as in pyloric and intestinal obstruction,
• Severe and prolonged diarrhea,
• Pyloric stenosis with severe vomiting,
• Haematemesis,
• Haemorrhage and shock; shock due to severe burns,
• Ulcerative colitis with severe chloride loss,

• In crisis of Addison’s disease (hypoadrenalism).
(b) Renal
The blood urea can be increased in all forms of kidney diseases like:
• In acute glomerulonephritis.
• In early stages of type II nephritis (nephrosis) the blood urea may not be increased,
but in later stages with renal failure, blood urea rises.
• Other conditions are malignant nephrosclerosis, chronic pyelonephritis and

mercurial poisoning.
• In diseases such as hydronephrosis, renal tuberculosis; small increases are seen but
depends on extent of kidney damage.
(c) Postrenal Diseases

These lead to increase in blood urea, when there is obstruction to urine flow. This
causes retention of urine and so reduces the effective filtration pressure at the
glomeruli; when prolonged, produces irreversible kidney damage.
Causes:
• Enlargement of prostate,
• Stones in urinary tract,
• Stricture of the urethra,
6
• Tumours of the bladder affecting urinary flow.
Note
Increase in blood urea above normal is called uraemia.
3- Decreased levels: are rare, but may be seen in:

• Some cases of severe liver damage.
• Physiological condition: blood urea is lower in pregnancy than in normal non
pregnant women.

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Lecture 4: Protein and Amino acid Metabolism by Dr. Sura A.

Urea Formation (Krebs-Henseleit cycle)

Steps of urea biosynthesis

Biosynthesis of urea or ornithine—urea cycle

Regulation of urea cycle

Disorders of Urea Cycle

Clinical significance of urea:

• Salt and water depletion,

• Severe and prolonged diarrhea,

• Pyloric stenosis with severe vomiting,

• Haemorrhage and shock; shock due to severe burns,

• Ulcerative colitis with severe chloride loss,

• Other conditions are malignant nephrosclerosis, chronic pyelonephritis and

(c) Postrenal Diseases

• Tumours of the bladder affecting urinary flow.

3- Decreased levels: are rare, but may be seen in:

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