Carbamoyl phosphate synthetase I

In E. coli the single CPS that carries out the functions of CPSI and CPSII is a heterodimer with a small subunit and a larger subunit with about 382 and 1073 amino acid residues in size, although in mammals (and other vertebrates) the CPSI protein is encoded by a single gene. The small subunit contains one active site for the binding and deamination of glutamine to make ammonia and glutamate. The large subunit contains two active sites, one for the production of carboxyphosphate, and the other for the production of carbamoyl phosphate. Within the large subunit there are two domains (B and C) each with an active site of the ATP-grasp family. ==Mechanism==

The overall reaction that occurs in CPSI is: 2ATP + HCO3− + NH4+ → 2ADP + Carbamoyl phosphate + Pi • Bicarbonate is phosphorylated to form carboxyphosphate • Ammonia attacks the carboxyphosphate, resulting in carbamate • Carbamate is phosphorylated to give carbamoyl phosphate Regulation CPSI is regulated by N-acetylglutamate which acts as an obligate allosteric activator of CPS1. NAG, by binding to domain L4, triggers changes in the A-loop and in Arg1453 that result in changing interactions with the T′-loop of domain L3, which reorganizes completely from a β-hairpin in the apo form to a widened loop in the ligand-bound form. In this last form, the T′-loop interacts also with the tunnel-loop and the T-loop of the L1 domain, thus transferring the activating information to the bicarbonate-phosphorylating domain. This interaction with NAG and a second interaction, with a nucleotide, stabilise the active form of CPSI. The necessity for this ligand also connects the high concentration of nitrogen, reflected in excess of glutamate and arginine to produce NAG, to an increase in CPSI activity to clear this excess. ==Metabolism==

CPSI plays a vital role in protein and nitrogen metabolism. Once ammonia has been brought into the mitochondria via glutamine or glutamate, it is CPSI's job to add the ammonia to bicarbonate along with a phosphate group to form carbamoyl phosphate. Carbamoyl phosphate is then put into the urea cycle to eventually create urea. Urea can then be transferred back to the blood stream and to the kidneys for filtration and on to the bladder for excretion. Disease Lack of or non-functional CPS1 due to mutation in the CPS1 gene on chromosome 2 that leads to carbamoyl phosphate synthetase I deficiency. CPS1 deficiency is an autosomal recessive metabolic disorder inherited from the mutation-carrier parents. When CPS1 functionality is absent, proteins and nitrogen are poorly, rather incompletely metabolised, resulting in high levels of ammonia in the body. This is dangerous because ammonia is highly toxic to the body, especially the nervous system, and can result in intellectual disability and seizures. The disease is rare and is estimated to occur one in 1.3 million people worldwide, but the condition is poorly recorded since most individuals with the disease die during infancy. ==Notes==