The Urea Cycle in Healthy Individuals
The urea cycle (Fig. 1) has two functions in the human metabolism. It is responsible for the de novo synthesis of arginine and converting waste nitrogen (ammonia) into urea, which can readily be excreted.8 Urea is made up of ammonia, nitrogen from aspartate, and carbon dioxide in the form of bicarbonate, allowing approximately 90% of waste nitrogen-containing compounds to be expelled in urine. In a healthy individual, the uric acid cycle goes through six enzyme reactions and two mitochondrial transporters to convert ammonia into a less toxic substance, such as urea or uric acid.2
The urea cycle, its steps, and essential enzymes. From Mitchell et al., 2009.
The cycle begins in the mitochondria where ammonia and bicarbonate react to produce carbamoyl phosphate.10 Once catalyzed by carbamoyl phosphate synthetase I (CPS1), the anion is able to enter the urea cycle.11 Throughout the cycle, carbamoyl phosphate is converted to citrulline, and then argininosuccinase with the help of a few specialized enzymes.1 In order to cleave the argininosuccinate in the fourth stage of the urea cycle, an enzyme called argininosuccinase must be present. This stage is situated in the cytosol of hepatic cells. If the enzyme is present, argininosuccinate is cleaved to generate arginine and fumarate. The arginine produced by this reaction is cleaved by arginase to form urea, which can be readily excreted.
The Urea Cycle in Diseased Individuals
If an individual has a deficiency in any of the six essential enzymes, they are diagnosed with a urea cycle disorder as a consequence.2 In the case of an argininosuccinate lyase deficiency, the enzyme argininosuccinase is scarce. As a key enzyme for the completion of stage four of the urea cycle, if it is lacking, the cycle is halted
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