Carbamoyl phosphate synthetase I (CPS1 or CPSI) is a ligaseenzyme located in the mitochondria involved in protein metabolism and the subsequent production of urea in animals. It transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme. Abnormal or loss of the enzyme leads to CPS1 deficiency, a severe and deadly metabolic disorders.
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.[1] 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.[2][3] Within the large subunit there are two domains (B and C) each with an active site of the ATP-grasp family.[1] Connecting the two subunits is a tunnel of sorts, which directs the ammonia from the small subunit to the large subunit.[4]
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.[n 1] 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.[6]
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 autosomalrecessivemetabolic 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,[7] but the condition is poorly recorded since most individuals with the disease die during infancy.[8]
↑Thoden JB, Holden HM, Wesenberg G, Raushel FM, Rayment I (May 1997). "Structure of carbamoyl phosphate synthetase: a journey of 96 A from substrate to product". Biochemistry. 36 (21): 6305–16. doi:10.1021/bi970503q. PMID9174345.
12Kim J, Raushel FM (May 2004). "Perforation of the tunnel wall in carbamoyl phosphate synthetase derails the passage of ammonia between sequential active sites". Biochemistry. 43 (18): 5334–40. doi:10.1021/bi049945+. PMID15122899.
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