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Detoxification of ammonia
A 55-year-old man suffers from cirrhosis of liver. Toxins such as ammonia are not properly metabolized by the liver and can damage brain. Which of the following compounds should be in highest concentration in brain as a result of detoxification of ammonia?
A. Alpha Ketoglutarate
D.GABA (Gamma amino butyric acid)
The correct answer is C-Glutamine
Ammonia is produced as a result of various metabolic activities. It has to be detoxified immediately else can prove toxic to the brain cells and other tissues.
Mechanism of Ammonia detoxification
1) The first line of defense- Glutamate condenses with ammonia to produce Glutamine. The reaction catalyzed can be represented as follows (figure-1)
Figure-1- Glutamate to Glutamine conversion is catalyzed by Glutamine synthetase. It is an energy requiring process, ATP acts as a source of energy.
Glutamine is transported to liver.The nitrogen of glutamine can be converted to urea in the liver (Figure -2).
Figure-2- Hydrolytic release of the amide nitrogen of glutamine as ammonia,is catalyzed by glutaminase in liver. Ammonia thus released is detoxified producing urea.
2) Second line of defense
In conditions of excess ammonia release the second line of defense involves the formation of Glutamate from Alpha ketoglutarate (intermediate of TCA cycle) that can be subsequently used for Glutamine synthesis as explained above . The reaction can be represented as follows :
Figure-3- Ammonia detoxification. In the first step the reaction is catalyzed by Glutamate dehydrogenase, a unique enzyme that can use either of NAD+ or NADP+ as a coenzyme. The reaction is reversible, but in the liver the reaction is directed towards Alpha ketoglutarate formation and the released ammonia is used for urea synthesis. Glutamate to Glutamine is an energy requiring irreversible reaction catalyzed by Glutamine synthetase.
Implication of Ammonia Intoxication
In the process of detoxification of Ammonia, some of the biologically important compounds are depleted whereas some are produced in highly excess amounts to cause toxicity.
Glutamine is the final product of detoxification which is transported out of the brain cells in exchange with tryptophan. Tryptophan is a precursor of Serotonin, the excess of which causes a state of hyper excitation.
Glutamate and Alpha ketoglutarate are depleted in this process of ammonia detoxification.
Decreased Glutamate, produces less GABA(figure-4), which is an inhibitory transmitter, thus again the result is a state of hyper excitation.
Figure-4- Glutamate is decarboxylated to produce Gamma AminoButyric acid (GABA). The reaction is catalyzed by Glutamate decarboxylase, that requires the presence of Vitamin B6.
The second compound that is decreased is Alpha ketoglutarate, an intermediate of TCA cycle and the depletion of which causes overall suppression of TCA cycle resulting in a state of energy depletion.
The symptoms of ammonia intoxication include- Slurring of speech, blurring of vision, tremors, convulsions,coma and death. The biochemical basis of such symptoms is energy depletion and hyperexcitation due to excess serotonin formation and decreased GABA synthesis. In Cirrhosis of liver, the conversion of ammonia to urea is impaired, the resulting hyperammonemia), proves toxic to brain. In severe liver disorders blood and CSF Glutamine levels are increased (a diagnostic feature of hepatic encephalopathy).
As regards other options
A. Alpha Ketoglutarate- its concentration is decreased, as explained above.
B. Glutamate- Its concentration is also decreased
C. Glutamine concentration is increased.
D.GABA (Gamma amino butyric acid)- levels are decreased.
E. Asparagine- levels are not much affected in ammonia intoxication.
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