metabolism of ammonia and its intoxicationjsmu.edu.pk/lectures/2018/sem4/20180718 lecture 2. ammonia...
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Metabolism of Ammonia
and its Intoxication
• Ammonia is produced by all tissues during metabolism.
• Ammonia is disposed of primarily by formation of urea in the liver
• Level of ammonia in the blood must be kept very low because even slightly elevated concentrations (Hyperammonemia) are toxic to the central nervous system
• Normal concentration: 25-40 mol/l (0.4-0.7 mg/l)
• Ammonia is toxic to the CNS therefore there must be a metabolic mechanism by which nitrogen is moved from peripheral tissues to the liver
Ammonia
Synthesis of Glutamine in Peripheral Tissue and Transport to the Liver
Summary of sources of ammonia for urea cycle
Transport of Ammonia in the circulation
• Although ammonia is constantly produced in the tissues. It
is present at very low levels in blood. This is due to both:
• The rapid removal of blood ammonia by the liver
• Several tissues particularly release amino acid nitrogen in
the form of glutamine or alanine rather than as free
ammonia
Transport of Ammonia
• Two ways of nitrogen transport from peripheral tissues (muscle) to the liver:
• Alanine cycle: Glutamate is formed by transamination reactions
Glutamate is not
deaminated in
peripheral tissues
The glucose–alanine cycle. P
age
98
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2. Nitrogen can be transported as glutamine.
2. Transportation of ammonia by Gln
CONH2
(CH2)2
CHNH2
COOH
Gln synthetaseCOOH
(CH2)2
CHNH2
COOH
+ NH3
ATP ADP + Pi
Glu GlnGlutaminase
H2O
• After transport in the bloodstream, the glutamine enters the liver and NH4 is liberated in mitochondria by the enzyme glutaminase.
Urea
• Formation of urea in the liver is the most important disposal route for ammonia. Urea travels in the blood from the liver to the kidney
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Major fate of waste nitrogen
O
H2N C NH2urea
Causes of Increased Plasma Level of Ammonia
l ) Decreased urea synthesis and inadequate removal of ammonia
2) Excessive generation of ammonia
Ammonia Intoxication
• This is essential since NH3 is toxic to central nervous system.
• In severely impaired hepatic function, cirrhois, ammonia intoxication develops.
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Krebs citric acid cycle
glutamine
g-aminobutyric acid
acetyl COA
NH3
Glutamic acid
Glycose Glucose-6-phosphate
Pyruvic acid
Lactic acid
Oxaloacetic acid
Citric acid
Succinic acid
a-Ketoglu- taric acid
ATP
Choline Acetylcholine
①Excessive consumption of a- ketoglutaric acid
→ hindering tricarboxylic acid cycle
③Inhibiting activity of pyruvic acid decarboxylase → generation of acetyl coenzyme A↓ →impairing TA cycle
Krebs citric acid cycle ④ Excessive consumption of ATP by synthesis of glutamine
② Excessive consumption reduced coenzyme I → hindering delivery of H+ in respiratory chain →ATP generation↓
l ) Interfering cerebral energy metabolism
ATP
ATP
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2) Changing neurotransmitter in the brain
① Excitative neurotransmitter↓
Glutamic acid consumed by combination with NH3
Inhibition of pyruvic acid decarboxylase by NH3
glutamine
g-aminobutyric acid
acetyl COA
NH3
Glutamic acid
Glycose Glucose-6-phosphate
Pyruvic acid
Lactic acid
Oxaloacetic acid
Citric acid
Succinic acid
a-Ketoglu- taric acid
ATP
Choline Acetylcholine
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.
3) Direct inhibitory effect on neural cell
membrane
Interfere membrane potential and excitation of neuron
by inhibiting Na+-K+-ATPase and competitively inhibit K+
enter cells.
Intoxication of ammonia on the brain Impairment of energy metabolism in brain
• ammonia reacts with α-ketoglutatrate to produce glutamate and glutamine
• consumption of α-ketoglutatrate, NADH and ATP, inhibition of pyruvate decarboxylase leading to the reduction of acetyl CoA and acetylcholine
Alteration of neurotransmitters
• Decreased excitatory neurotransmitters glutamate and acetylcholine
• Increased inhibitory neurotransmitters glutamine and gamma-aminobutyric acid
Inhibiting action on nerve cell membrane
Severe hepatic dysfunction
Urea synthesis
hyperammonemia
Elevated level of brain ammonia
Brain dysfunction
Summary of ammonia intoxication
• Symptoms:
• Tremor, slurred speech, blurred vision, coma
• When ammonia concentration increases in blood and other biological fluİds, it diffuses across blood-brain barrier. It can cause comma and death
Hyperammonemia
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