Transcript Detoxification of ammonia and biosynthesis of urea

Detoxification of
ammonia and
biosynthesis of urea.
The basic features of nitrogen
metabolism were elucidated
initially in pigeons
AMMONIA METABOLISM
The ways of ammonia formation
1. Oxidative deamination of amino acids
2. Deamination of physiologically active amines and nitrogenous
bases.
3. Absorption of ammonia from intestine (degradation of
proteins by intestinal microorganisms results in the ammonia
formation).
4. Hydrolytic deamination of AMP in the brain (enzyme –
adenosine deaminase)
Ammonia is a toxic substance to plants and animals
(especially for brain)
Normal concentration: 25-40 mol/l (0.4-0.7 mg/l)
Ammonia must be removed from the organism
Terrestrial vertebrates
synthesize urea (excreted by
the kidneys) - ureotelic
organisms
Birds, reptiles synthesize uric
acid
Urea formation takes place in
the liver
Peripheral Tissues Transport Nitrogen to the Liver
Two ways of nitrogen transport from peripheral
tissues (muscle) to the liver:
Glutamate is
1. Alanine cycle. Glutamate is
not deaminated
in peripheral
formed by transamination reactions
tissues
Nitrogen is then transferred to pyruvate to
form alanine, which is released into the blood.
The liver takes up the alanine and converts it back
into pyruvate by transamination.
The glutamate formed in the liver is deaminated
and ammonia is utilized in urea cycle.
2. Nitrogen can be transported as glutamine.
Glutamine synthetase catalyzes the synthesis of
glutamine from glutamate and NH4+ in an ATPdependent reaction:
THE UREA CYCLE
Urea cycle - a cyclic pathway of urea synthesis
first postulated by H.Krebs
The sources of
nitrogen atoms in
urea molecule:
- aspartate;
- NH4+.
Carbon atom
comes from CO2.
The free ammonia is coupling with carbon dioxide to
form carbamoyl phosphate
Two molecules of ATP are required
Reaction takes place in the matrix of liver
mitochondria
Enzyme: carbamoyl phosphate synthetase (20 % of
the protein of mitochondrial matrix)
Carbamoyl
ornithine
phosphate
donates
carbamoyl
group
to
The product - citruilline
Enzyme: ornithine carbamoyltransferase
Reaction takes place in the mitochondrial matrix
Citrulline leaves the matrix and passes to the cytosol
In the cytosol citrulline in the presence of ATP
reacts with aspartate to form argininosuccinate
Enzyme: argininosuccinate synthetase
Argininosuccinate is cleaved to free arginine and
fumarate
Enzyme: argininosuccinate lyase
The fumarate enters the tricarboxylic acid cycle
Arginine is hydrolyzed to generate urea and ornithine
Enzyme: arginase (present only in liver of ureotelic
animals)
Ornithine is transported back into the mitochondrion
to begin another cycle
Urea is excreted (about 40 g per day)
The Linkage between Urea Cycle, Citric Acid Cycle
and Transamination of Oxaloacetate
Fumarate formed in urea cycle enters citric acid cycle
and is converted to oxaloacetate.
Fates of oxaloacetate:
(1) transamination to aspartate,
(2) conversion into glucose,
(3) condensation with acetyl CoA to form citrate,
(4) conversion into pyruvate.