Ammonia and Urea Cycle

Ammonia and Urea cycle
DR. DARWIISH
Introduction
A. Ammonia is a toxic substance especially to the central
nervous system. Ammonia is constantly being
liberated in the metabolism of amino acids (mostly)
and other nitrogenous compounds. At the
physiological pH, ammonia exists as ammonium
(NH4 ) ion
B. Any ammonia formed in the peripheral tissue must be
moved to the liver to be converted into urea. This
maintains ammonia at low level in circulating blood
C. Blood ammonia: blood contains traces of ammonia:
10-80 ug/dl
Formation of ammonia
The production of NH3 occurs from the amino acids
( transamination and deamination), biogenic amines, amino
group of Purines and Pyrimidines and by the action of
intestinal bacteria (urease) on urea.
Transport and storage of NH3
Despite a regular and constant production of NH3 from various tissues,
its concentration in the circulation is surprisingly low( normal plasma
10-80 ug/dl).
This is mostly because the body has an efficient mechanism for NH3
transport and its immediate utilization for urea synthesis.
Role of glutamine is a storehouse of NH3. it is present at the highest
concentration (8mg/dl in adults)
Sources of ammonia
Glutamine : the
kidneys form Purines and
Transdeamination ammonia from
pyrimidines
of amino acids glutamine by
glutaminase metabolism
enzyme
In intestine ,
Various nitrogenous
ammonia is
compounds e.g Dietary amino
produced by the
monoamines that
acts as
action of intestinal acids
bacterial enzymes
neurotransmitters
by:
Urea secreted
into the intestine
Function of ammonia
Ammonia is not just a waste product of nitrogen
metabolism. It involved (directly or via glutamine) for the
synthesis of many compounds in the body.
These include non-essential amino acids ,

purines ,pyrimidines amino sugars, asparagine etc.
Ammonium ions ( NH4) are very important to maintain

acid-base balance of the body.
Toxicity of ammonia
Even a marginal elevation in the blood ammonia
concentration is harmful to the brain.
Ammonia, when it accumulates in the body, results in
slurring of speech and blurring of the vision and causes
tremors.
It may lead to coma and, finally, death, if not corrected
Hyperammonemia : Elevation in blood NH3 level may
be genetic or acquired.
Impairment in urea synthesis due to a defect in any one of
the five enzymes is described in urea synthesis.
All these disorders lead to hyper-
ammonemia and cause mental
retardation.
The acquired hyper-ammonemia may be
due to hepatitis, alcoholism etc.
Where the urea synthesis becomes
defective, hence NH3 accumulates.
Explanation for NH3 toxicity : The
reaction catalysed by glutamate
dehydrogenase probably explains the
toxic affects of NH3 in brain.
Urea is the end product of protein metabolism
(amino acid metabolism).
The nitrogen of amino acids, converted to
ammonia (as described above), is toxic to the
body.
It is converted to urea and detoxified.
Urea cycle As such, urea accounts for 80-90% of the nitrogen
containing substances excreted in urine.
Urea is synthesized in liver and transported to
kidneys for excretion in urine.
Urea cycle is the first metabolic cycle that was
elucidated by Hans Krebs and Kurt Henseleit
(1932), hence it is known as Krebs-Henseleit cycle
.
Site of urea formation
1. Liver is the only site for urea formation
2. Six amino acids share in urea cycle: ornithine,citrulline,
arginosuccinate,aspartate and arginine.the 6 th one is N-
acetyglutamate that acts as allosteric activator of carbamoyl
phosphate synthase 1
3. Then urea is transported by the blood to the kidney to be excreted in
urine (urine urea is 20-40 g/day)
Plasma urea:
a. Plasma urea is 15-45 mg/dl
b. Diagnostic importance of plasma urea determination:-
 Measurement of plasma urea is one of the kidney function tests
 In kidney diseases as in renal failure, kidney fails to excrete urea-
High blood urea concentration (uremia)
1. Formation of Carbamoyl
phosphate:
a. This reaction occurs in mitochondria
b. It needs CO2 ( a product of citric acid
cycle), ammonia ( a product of
deamination of glutamate) and
phosphate ( from ATP).
Steps: c. This reaction is catalyzed by
carbomoyl phosphate synthase I. it
needs magnesium (mg++) ions,
manganese (Mn++) and N-
acetylglutamate as activators
d. 2 ATP molecules are used in this
reaction, one to provide phosphate
and the other to supply energy
2. Formation of citrulline:
a. This reaction also occurs in mitochondria
b. Carbamoyl phosphate reacts with ornithine in the presence of
ornithine transcarbamoylase enzyme producing citrulline
c. Citrulline then passes to cytosol
d. Ornithine is regenerated with each turn of urea cycle
3. Formation of arginosuccinate:
e. Citrulline reacts with aspartate in the cytosol to form
arginosuccinate
4. Cleavage of arginine into ornithine and urea:
f. Orgithine then passes to the mitochondria to start a new cycle
g. Urea passes to the blood to be excreted by the kidney in urine
Overall reaction and energetics
The urea cycle is irreversible and consumes 3 ATP.
Two ATP are utilized for the synthesis of carbamoyl phosphate.
One ATP is converted to AMP and PPi to produce
arginosuccinate which equals to ATP.
Regulation of urea cycle:
The first reaction catalysed by carbamoyl phosphate synthase 1 (CPS
l) is rate limiting reaction or committed step in urea synthesis.
CPS I is allosterically activated by N-acetylglutamate (NAG).
lt is synthesized from glutamate and acetyl CoA by synthase and
degraded by a hydrolase (Fig.l 5.1 l).
Relationship between tricarboxylic acid cycle (TCA) and urea
cycle:
1. C02 needed for urea formation is mostly produced in TCA.
2. Fumarate produced in urea cycle can be oxidized in TCA.
3· Aspartate can give oxaloacetate and vice versa (transamination).
4· ATP needed for urea cycle is derived from TCA

Ammonia and Urea Cycle

Uploaded by

Copyright:

Available Formats

Ammonia and Urea Cycle

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Ammonia and Urea Cycle

Uploaded by

Copyright:

Available Formats

Ammonia and Urea cycle

These include non-essential amino acids ,

Ammonium ions ( NH4) are very important to maintain

You might also like