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Animals excrete excess nitrogen in 3 major forms: ammonia, uric acid, and urea. Mammals are ureotelic organisms, which means that they are dependent on the synthesis and excretion of urea to maintain nitrogen balance. The urea cycle (also called the ornithine cycle), first described in 1932 by Hans Krebs and Kurt Henseleit, converts waste nitrogen derived from dietary protein and amino acid catabolism into urea. The urea cycle consists of a cofactor synthesizing enzyme (N-acetylglutamate synthase [NAGS]), 5 catalytic enzymes (carbamoyl-phosphate synthase 1 [CPS1], ornithine transcarbamylase [OTC], argininosuccinate synthase 1 [ASS1], argininosuccinate lyase [ASL], and arginase 1 [ARG1]), and 2 transporters (mitochondrial aspartate/glutamate carrier SLC25A13 or citrin and mitochondrial ornithine transporter ORNT1 or SLCA15) that facilitate the transfer of nitrogen from ammonia and aspartate to urea (Fig. 141-1). The initial 2 catalytic reactions occur within the mitochondria, whereas the remaining reactions, including the generation of urea, occur in the cytosol. The complete urea cycle exists only in the liver, although certain enzymatic components of the urea cycle (eg, ASS1 and ASL) are also expressed in a variety of other tissues.

Figure 141-1

The urea cycle. The nitrogen from ammonia and aspartate (black circles) is transferred to urea via the enzymes (depicted in blue) and transporters (depicted in red) of the urea cycle. Ornithine that contains 2 nitrogen atoms (yellow circles) is recycled, and hence, the urea cycle is also called the ornithine cycle. ARG1, arginase 1; ASL, argininosuccinate lyase; ASS1, argininosuccinate synthase 1; citrin, mitochondrial aspartate/glutamate carrier; CPS1, carbamoyl-phosphate synthase 1; NAGS, N-acetylglutamate synthase; ORNT1, mitochondrial ornithine transporter; OTC, ornithine transcarbamylase.

NAGS synthesizes N-acetylglutamate, a cofactor required for the allosteric activation of CPS1 that catalyzes the first and rate-limiting step of the urea cycle. CPS1 synthesizes carbamoyl-phosphate from ammonia and bicarbonate, and in this step, the first atom of waste nitrogen enters the urea cycle (see Fig. 141-1). Carbamoyl-phosphate and ornithine are converted to citrulline by the enzyme OTC, and citrulline is actively transported out of the mitochondria by the ornithine transporters (ORNT1 or SLC25A15 and ORNT2 or SLC25A2). The second atom of waste nitrogen enters the urea cycle in the form of aspartate. Citrin, the mitochondrial aspartate/glutamate carrier, transports aspartate across the mitochondrial membrane into the cytosol. ASS1 conjugates citrulline and aspartate to form argininosuccinic acid, which is cleaved by ASL into fumarate and arginine. In the final step of the urea cycle, ARG1 hydrolyzes arginine into urea and ornithine. The ornithine is transported back into the mitochondria by ORNT1.

More than 90% of nitrogen derived from dietary sources and protein catabolism is not used for anabolic processes and must be excreted as urea. Deficiency of one of the urea cycle enzymes or transporters leads to a urea cycle disorder (UCD). UCDs are a group ...

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