Citrulline reactions, with aspartate

The second NH2 group of the later urea molecule is provided by aspartate, which condenses with citrulline into argininosucci-nate. ATP is cleaved into AMP and diphosphate (PPi) for this endergonic reaction. To shift the equilibrium of the reaction to the side of the product, diphosphate is removed from the equilibrium by hydrolysis. 

This enzyme [EC 6.3.4.S], also referred to as citrul-line aspartate ligase, catalyzes the reaction of citrulline with aspartate and ATP to produce argininosuccinate, AMP, and pyrophosphate (or, diphosphate). 

FIGURE 20.6 M EC HAN ISM Mechanism of step 2 in the urea cycle, the reaction of citrulline with aspartate to give argininosuccinate. 

Nitrogen 1 of the purine ring originated from the amino group of aspartic acid by analogous reactions [Eqs. (11) and (9)], except that ATP replaced GTP in the condensation reaction with aspartic acid. Also, in urea synthesis, the formation of aiginosuccinic acid from citrulline and aspartic... 

In the hepatic cytosol, citrulline reacts with aspartate to form argininosuccinate, catalyzed by argininosuccinate synthetase (AS Fig. 40-5 reaction 3). The mRNA for this enzyme is increased by starvation, corticosteroids or cyclic-AMP. Citrulline itself potently induces the mRNA. 

The answer is C. Pyruvate kinase deficiency is ruled out by the elevated serum lactate levels. The coma is associated with a fasting hypoglycemia, which is indicative of pyruvate carboxylase deficiency. The elevated citrulline and lysine in the serum are due to a reduction of aspartic acid levels, which are caused by the reduced levels of oxaloacetate, the product of the pymvate carboxylase reaction. 

In the urea cycle ammonia is first combined with C02 to form carbamoyl phosphate. This then combines with ornithine to form citrulline. Citrulline then condenses with aspartate, the source of the second nitrogen atom in urea, to form argininosuccinate. This compound is in turn split to arginine and fumarate, and the arginine then splits to form urea and regenerate ornithine The first two reactions take place in the mitochondria of liver cells, the remaining three in the cytosol. 

Once citrulline is in the cytosol, argininosuccinic acid is formed by condensation of citrulline with aspartate. This is where the second nitrogen atom enters the cycle. Argininosuccinate synthetase, a homotetramer of a 46-kd polypeptide catalyzes the reversible reaction accompanied by hydrolysis of ATP to AMP and pyrophosphate. The subsequent hydrolysis of pyrophosphate shifts the equilibrium to the right and results in the consumption of two high-energy phosphate bonds. 

Citrulline combines with aspartate to form argininosuccinate in a reaction that is driven by the hydrolysis of ATP to AMP and inorganic pyrophosphate. 

Step 3. Citrulline is transported into the cytoplasm and now condenses with aspartate to produce argininosuccinate. This reaction, which requires energy released by the hydrolysis of ATP, is catalyzed by the enzyme argininosuccinate synthase. 

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