ureumcyclus

Ureumcyclus, or the urea cycle, is a metabolic pathway in the liver of ureotelic animals that detoxifies ammonia, a byproduct of amino acid metabolism, by converting it into urea for excretion in urine. In humans and many mammals, the cycle operates primarily in hepatocytes and serves as the main route for nitrogen disposal.

The cycle begins in mitochondria with carbamoyl phosphate synthetase I (CPS1) forming carbamoyl phosphate from ammonia and bicarbonate; CPS1 is allosterically activated by N-acetylglutamate. Carbamoyl phosphate then combines with ornithine via ornithine transcarbamylase (OTC) to form citrulline, which is transported to the cytosol. There, argininosuccinate synthetase adds aspartate to citrulline to form argininosuccinate, which is cleaved by argininosuccinase into arginine and fumarate. Arginase hydrolyzes arginine to urea, releasing ornithine to re-enter mitochondria and continue the cycle. The process consumes energy, typically four high-energy phosphate bonds per urea molecule formed.

The cycle connects nitrogen disposal with central carbon metabolism because fumarate can enter the TCA cycle and aspartate derives from oxaloacetate. Regulation hinges on CPS1 activation by N-acetylglutamate, whose production responds to arginine levels and amino acid balance. The ureumcyclus is essential to prevent ammonia accumulation; defects in any enzyme of the cycle can cause hyperammonemia with potential for encephalopathy.

Clinical relevance includes inherited deficiencies (e.g., CPS1, OTC, argininosuccinate synthetase, argininosuccinate lyase, arginase) and related metabolic disorders. Diagnosis relies on amino acid and ammonia measurements; treatment combines dietary management, nitrogen-scavenging therapies, and, in severe cases, liver transplantation. The cycle is historically linked to the Krebs–Henseleit work and is also known as the ornithine cycle.