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A 10-month-old infant was admitted to the hospital in a state of coma. Examination revealed a high body temperature, rapid pulse rate, abnormal electroencephalogram and hepatomegaly. Analysis of his urine showed abnormally high amounts of glutamine and uracil, which suggested a high blood ammonium ion concentration. Considering the data, which enzyme might be defective in this patient?

A. Arginase

B. Carbamoyl phosphate synthetase I

C. Glutamate dehydrogenase

D. Glutaminase

E. Ornithine transcarbamoylase

The correct answer is- E- Ornithine Transcarbamoylase.

High amounts of glutamine in blood, urine or CSF indicate underlying hyperammonemia.

Glutamine is produced during the course of detoxification of ammonia.

Hyperammonemia and Glutamine levels

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):

Glutamine synthetase

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 keto glutarate (intermediate of TCA cycle) that can be subsequently used for Glutamine synthesis (as explained above and also shown below). The reactions can be represented as:

Detoxification of ammonia

Figure-3-Steps of detoxification of ammonia. In the first step the reaction is catalyzed by Glutamate dehydrogenase, a unique enzyme that can use any of NAD+ or NADP+ as a coenzyme. The reaction is although reversible, but in the liver the reaction is directed towards Alpha keto glutarate formation and the released ammonia is used for the urea formation. In conditions of hyperammonemia, the reaction is favored towards glutamate formation. Glutamate to Glutamine is an energy requiring irreversible reaction catalyzed by Glutamine synthetase.


Thus, Glutamine is the end product of detoxification of ammonia; therefore the glutamine levels are directly proportional to the ammonia levels.

Overview of causes of hyperammonemia

There can be congenital or acquired causes of hyperammonemia. Urea cycle disorders are responsible for congenital hyperammonemia, whereas the cirrhosis of liver or other conditions causing liver failure are responsible for Acquired hyperammonemia.

The symptoms of ammonia intoxication include- Slurring of speech, blurring of vision, tremors, convulsions, coma and death. The symptoms are due to energy depletion (TCA cycle suppression due to depletion of alpha ketoglutarate) and hyperexcitation caused as a result of excess serotonin (excitatory)  but decreased GABA (gamma amino butyric acid- inhibitory neurotransmitter) formation.

Hyperammonemia and urea cycle disorders

The deficiencies of urea cycle enzymes cause hyperammonemia and corresponding increase in glutamine levels.

In the given case the clinical manifestations are indicative of hyperammonemia due to a defect in the urea cycle, and the simultaneous rise of uracil in urine indicates excess pyrimidine biosynthesis, that might be due to divergence of unutilized Carbamoyl-P towards the pathway of pyrimidine biosynthesis. The Carbamoyl-phosphate accumulates only if there is deficiency of Ornithine transcarbamoylase. The mitochondrial Carbamoyl-P leaks into the cytoplasm so as to be channeled towards pathway of pyrimidine biosynthesis (figure-4).


Figure-4- Urea cycle disorder causing orotic aciduria. Ornithine transcarbamoylase deficiency leaves excess of Carbamoyl -P that acts as a substrate for pyrimidine biosynthesis.

As regards other options

A. Arginase- Catalyzes the conversion of Arginine to urea and ornithine (figure-4)

B. Carbamoyl phosphate synthetase I- catalyzes the first step of urea cycle. It is a rate limiting enzyme. There is a cytoplasmic Carbamoyl-P synthetase-II, which is the first enzyme of pathway of pyrimidine pathway. Thus Carbamoyl P is produced both in the urea cycle as well in the pyrimidine biosynthetic pathway by different enzymes. The mitochondrial Carbamoyl P, as in this case, can leak to cytoplasm to be subsequently utilized for pyrimidine biosynthesis if there is a block at the level of its utilization forming Citrulline in urea cycle.

C. Glutamate dehydrogenase- The reaction catalyzed by Glutamate dehydrogenase has been shown above (figure-3)

D. Glutaminase- Catalyzes the hydrolysis of Glutamine to glutamate (figure-2).

Thus ornithine transcarbamoylase deficiency is the most appropriate answer. Hyperammonemia and rise in glutamine levels can be observed in other urea cycle disorders as well but the simultaneous rise of orotic acid or uracil nucleotide in urine occurs only in ornithine transcarbamoylase deficiency.




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