Answer- Case study- Hyperammonemia and orotic aciduria

A newborn becomes lethargic and drowsy 24 hour after birth. Blood analysis shows hyperammonemia, coupled with Orotic aciduria. This individual has an enzyme deficiency that leads to an inability to directly produce which of the following?

A. Carbamoyl phosphate

B. Ornithine

C. Citrulline

D. Argininosuccinate

E. Arginine

Answer- The correct answer is -C-Citrulline.

Orotic aciduria refers to an excessive excretion of Orotic acid in urine. This is a disorder of pathway of pyrimidine biosynthesis inherited in an autosomal recessive manner. Increased excretion of orotic acid, uracil, and uridine also accompanies a deficiency in liver mitochondrial ornithine transcarbamoylase, an enzyme of urea cycle that catalyzes the conversion of ornithine to citrulline.

There is no direct link between urea cycle and pyrimidine biosynthetic pathway, but channeling of metabolites of urea cycle to pyrimidine biosynthetic pathway can occur due to block at the level of Ornithine transcarbamoylase (Figure)

There are two isoforms of enzyme Carbamoyl phosphate synthetase; I and II. Carbamoyl Phosphate synthetase I (mitochondrial) catalyzes the first step of urea formation, the resultant carbamoyl- P, condenses with ornithine to form citrulline (figure) in the presence of ornithine transcarbamoylase.

The cytosolic Carbamoyl phosphate synthetase-II catalyzes the first step of pyrimidine biosynthesis and the resultant carbamoyl- P, condenses with Aspartate to form Carbamoyl Aspartate, the reaction is catalyzed by Aspartate transcarbamoylase.

In ornithine transcarbamoylase deficiency excess carbamoyl phosphate exits to the cytosol, where it acts as a substrate for aspartate transcarbamoylse and  stimulates pyrimidine nucleotide biosynthesis causing orotic aciduria.

Orotic aciduria in OTC deficiency

Figure- Urea cycle defect and orotic aciduria

As regards other options (figure) Carbamoyl -P is formed by the action of CPS-I. Ornithine is generated at the last step of urea cycle by the action of Arginase enzyme, that can be reutilized, thus it acts as a catalyst.

Argino succinate is formed by the action of Argino sucinate synthetase, whereas Arginine is formed by the action of Argino succinate lyase. Deficiencies of these enzymes are not manifested as orotic acid uria.

Thus the correct option of -C, Citrulline, the formation of which is impaired in the deficiency of ornithine transcarbamoylase.

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