Carbamoyl phosphate citrulline, synthesis

Ornithine and citrulline are amino acids, but they are not used as building blocks of proteins. The formation of NH4 + by glutamate dehydrogenase, its incorporation into carbamoyl phosphate, and the subsequent synthesis of citrulline take place in the mitochondrial matrix. In contrast, the next three reactions of the urea cycle, which lead to the formation of urea, take place in the cytosol. 

Fermentation of arginine via citrulline and carbamoyl phosphate represents an additional mechanism of energy conservation resulting in ATP synthesis. This substrate-level phosphorylation does not require membrane-bound enzyme systems. 

In the biosynthesis of both pyrimidine and urea (or arginine) (Chapter 17), carbamoyl phosphate is the source of carbon and nitrogen atoms. In pyrimidine biosynthesis, carbamoyl phosphate serves as donor of the carbamoyl group to aspartate with the formation of carbamoyl aspartate. In urea synthesis, the carbamoyl moiety of carbamoyl phosphate is transferred to ornithine, giving rise to citrulline. 

In children, deficient levels of ornithine carbamoyitransferase (an enzyme involved in the urea cycle, and which converts ornithine and carbamoyl phosphate to citrulline) [218,220] present as orotic aciduria, a secondary effect resulting indirectly from the accumulation of carbamoyl phosphate. The deficiency of ornithine carbamoyitransferase leads to overall stimulation of pyrimidine synthesis de novo which is reflected by an increased production and excretion of orotic acid. 

Under many conditions the rate-limiting step in urea synthesis is the carbamoyl phosphate synthase reaction. Isolated liver mitochondria will synthesize citrulline from added ammonia under appropriate conditions. The rate of citrulline synthesis can be shown to depend on the intramitochondrial content of acetylglutamate, and both the mitochondrial acetylglutamate content and the rate of citrulline synthesis increase on adding glutamate to the mitochondria. 

STEPS 1-2 OF FIGURE 20.5 ARCININOSUCCINATE SYNTHESIS The urea cycle begins with a nucleophilic acyl substitution reaction of the nonprotein amino acid ornithine with carbamoyl phosphate to produce citrulline. The side-chain -NH2 group of ornithine is the nucleophile, phosphate ion is the... 

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