Urea cycle (vertebrate hepatic ureagenesis, Krebs-Henseleit cycle)

The urea cycle (ornithine cycle / Krebs-Henseleit cycle) is the principal pathway for the detoxification of waste nitrogen in ureotelic vertebrates, converting ammonia (arising largely from amino-acid catabolism) plus bicarbonate and aspartate-derived nitrogen into urea for renal excretion. In mammals it operates predominantly in periportal hepatocytes and spans two compartments: the first two committed steps are mitochondrial and the last three are cytosolic, so the pathway is physically split across the inner mitochondrial membrane and requires two dedicated mitochondrial carriers. The cycle proper comprises six enzymes. N-acetylglutamate synthase (NAGS) produces N-acetyl-L-glutamate (NAG), the obligate allosteric activator of carbamoyl phosphate synthetase 1 and therefore the regulatory gate of the whole pathway. Carbamoyl phosphate synthetase 1 (CPS1) condenses ammonia, bicarbonate and two ATP into carbamoyl phosphate in the matrix. Ornithine transcarbamylase (OTC) transfers the carbamoyl group to L-ornithine to give L-citrulline. Citrulline is exported to the cytosol in exchange for ornithine by the mitochondrial ornithine/citrulline carrier SLC25A15 (ORNT1). In the cytosol argininosuccinate synthase (ASS1) condenses citrulline with L-aspartate (the second nitrogen donor, supplied to the cytosol by the citrin aspartate/glutamate carrier SLC25A13) at the expense of ATP to form argininosuccinate; argininosuccinate lyase (ASL) cleaves this to L-arginine and fumarate; and arginase 1 (ARG1) hydrolyses arginine to urea and L-ornithine, regenerating the ornithine that re-enters mitochondria to close the cycle. The fumarate released by ASL links the urea cycle to the TCA cycle and, via aspartate regeneration, to the "aspartate-argininosuccinate shunt". Inherited deficiency of any of the six enzymes, of the two transporters (SLC25A15, SLC25A13), or of NAGS causes a urea cycle disorder presenting with hyperammonemia. The same enzyme chemistry, used biosynthetically rather than for nitrogen disposal, also produces arginine de novo (the arginine biosynthetic pathway) in tissues and organisms lacking a complete ureotelic cycle.